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Pharmacokinetics and Bioequivalence of Cefixime in Healthy Male and

Female Volunteers

By

Muhammad Mudassar Ashraf

B.Pharm., M.Phil.

A thesis submitted in partial fulfillment

of the requirements

for the degree of

DOCTOR OF PHILOSOPHY

IN

PHARMACOLOGY

Institute of Pharmacy, Physiology & Pharmacology,

University of Agriculture, Faisalabad,

Pakistan.

2015

5

DECLARATION

I hereby declare that the contents of the thesis, “Pharmacokinetics and Bioequivalence of

Cefixime in Healthy Male and Female Volunteers” are product of my own research and no

part has been copied from any published source (except the references, standard mathematical or

genetic models/equations/formulae/protocols etc.). I further declare that this work has not been

submitted for award of any other diploma/degree. The university may take action if the

information provided is found inaccurate at any stage.

MUHAMMAD MUDASSAR ASHRAF

6

The Controller of Examinations,

University of Agriculture,

Faisalabad.

"We, the Supervisory Committee certify that the contents and form of thesis submitted by

Mr. Muhammad Mudassar Ashraf, 2010-ag-74, have been found satisfactory and recommend

that it be processed for evaluation by the External Examiner(s) for the award of degree".

Supervisory Committee:

CHAIRMAN: _________________________________

(Prof. Dr. IjazJavedHasan)

MEMBER: _________________________________

(Dr. Bilal Aslam)

MEMBER: _________________________________

(Prof. Dr. TanweerKhaliq)

7

To

The persons who

Encourage, help and support others,

Make a smile on the faces of others

and

Bring happiness and joys in other’s life

8

ACKNOWLEDGMENT

All thanks to Almighty Allah, The Compassionate and The Merciful, who knows whatever is

there in the Universe hidden or evident and who bestowed upon me the intellectual ability to

complete this research work successfully. Trembling lips and wet eyes praise for our beloved

Holy Prophet Muhammad (Sal-Allaho Alaihe Wasallam) for the internal and external blessings

for the literate, illiterate, rich, poor, weaker, stronger, able, disabled and deserted human beings.

I express my heartfelt gratitude to my learned Supervisor, Professor Dr. Ijaz Javed Hasan

for giving me the opportunity to undertake a doctorate research study under his guidance,

kindness, skillful suggestions, constructive criticism and encouragement throughout the course of

this study and his patience during the research and writing of this thesis. In-spite of his busy

schedule, he always acted as a real spiritual teacher and provided guidance and valuable

suggestions throughout my research efforts and write up of this manuscript. Under his kind

supervision this work was converted into a write up getting its present shape. Being his student is

the best step happened in my career. I am always amazed by his vision, energy, patience and

dedication to the research and his students. He trained me to grow as a scientist and as a person.

It took all his efforts to raise me as a professional scientist in pharmacology field.

I communicate my heartiest gratification to the respectable members of my Supervisory

Committee, Professor Dr. Tanveer Khaliq, Director, Institute of Pharmacy, Physiology and

Pharmacology, Faculty of Veterinary Science and Dr. Bilal Aslam for their guidance, incentive

teaching, positive criticism, expertise advice and very insightful, beneficial and constructive

suggestions during the course of my studies and to improve this research project. Also with deep

sense of honour, I say a bundle of thanks to Dr. Faqir Muhammad for their valuable suggestions

in completion of my Ph.D. coursework, seminar, synopsis defense, comprehensive exam and

present endeavor. I also appreciate the nice behavior of other faculty members including teaching

staff, clerical staff, lab attendants, office boys and sweepers.

Hearty appreciations are also due to my seniors (Dr. Haseeb, Dr. Tariq and all others),

juniors (Nasir, Majid Anwar, Batool Pirooz, Irum Nisar and all others) and all other well-wishers

specially Ahmad, Ahsan and Bilal Ashiq who never failed in helping me whenever their

assistance was needed. I take this opportunity to express my deep sense of gratitude to my old

respected teachers such as Dr. Naeem, Arshad, Shoukat, Asif Nadeem, Shoib Hakeem and Prof.

Dr. Saeed-ul-Hassan. I offer my sincere and cordial thanks for my friends Dr. Ehsan, Shafiq,

Usman and Zia who tried their best for arrangement of standard drug and HPLC facilities and

arrangements for me to execute this project. Many Prays and bundle of thanks to all the

volunteers (especially Mr. Saleem) who served themselves for my research project.

Last but not least, I also express my profound admiration to my precious family

members, especially to my father and mother, who have always believed in me, for their best

wishes and moral support during this whole period, with great patience even in presence of

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severe financial crisis with a great load of responsibilities of my home and youngsters. I would

not be where I am today without their love and Prayers. It is with sincere gratitude to both of

them for their continuous interest, encouragement and inspiration. They always provided me an

atmosphere conductive to the pursuit to my academic goals, from my childhood up till now. I

attribute my sincere love and care to all my younger brothers and sisters who made possible the

accomplishment of this academic program with their maximum input and role in domestic life

management. I also love my uncle, Tariq Saleem, for his guidance throughout my professional

and higher educational period. I can never pay my all the blood relations, relatives and friends

for their Prays and well wishes for me.

At the end, my little angel, my baby doll, my cute daughter, Urwah Zainab whose great

smile, laugh, voice, weeping sound, body gestures, playing with little hands and legs, moving

and staring with attractive eyes and all her other styles always gave me a spirit and new

refreshment even when I was fully tired and fed up, during last few months of my research

phase. Finally I would like to extend my appreciation to my beloved, my life and my wife, Dr.

Umbreen for all her timeously encouragement and assistance as well as the support. I would not

have been able to face my challenges without her who enabled me to complete my Ph.D.

efficiently and proficiently. She always tried her best to stand with me during my entire crisis

and paid her full attention to me and my family with love and respect, whatever the condition is.

From whom I always expect to do all the best for my beloved relations more than I do or I can. I

would like to thank her also for her encouragement, tolerance and understanding, as weIl as, for

making me a proud "Daddy" during the course of this academic program. Whole remains

incomplete if I don’t discuss her and record my sincerest thanks to her with full of Praise and

Prays.

They all waited for a period of about five years with great patience in cool and soft way

for completion of my degree only for me and my career. I also completed my degree only for all

of them, with full attention and dedication. Whenever I lost my heart, it was only the thought of

all of them which gave me a new courage to carry on and move to my target. My existence is

with all of them and I am nothing without their love, kindness, encouragement and support. For

whom I want to earn only to the limit by which I can give them a prosperous life with fulfillment

of all basic needs. Again love you forever.

This thesis is acknowledged to the patience, long wait, sincerity, love, support, help,

encouragement, motivation, well wishes and Prays of all of them.

(Muhammad Mudassar Ashraf)

10

TABLE OF CONTENTS

CHAPTER NO. TITLE PAGE NO.

LIST OF FIGURES i

LIST OF TABLES iii

LIST OF APPENDICES Vii

ABSTRACT Viii

I INTRODUCTION 1

II REVIEW OF LITERATURE 3

III MATERIALS AND METHODS 116

IV RESULTS 129

V DISCUSSION 175

VI SUMMARY 188

REFERENCES 191

APPENDICES 233

11

LIST OF FIGURES

FIGURE NO. TITLE PAGE NO.

.12 Chemical structure of cefixime 31

.22 Chemical structure of cefixime tri-hydrate 32

1.a3 Chromatogram of blank plasma of healthy

volunteer 122

1.3b Chromatogram of 1 µg/ml of cefixime standard 122

1.c3 Chromatogram of 2 µg/ml of cefixime standard 123

1.d3 Chromatogram of 3 µg/ml of cefixime standard 123

1.e3 Chromatogram of 4 µg/ml of cefixime standard 124

1.f3 Chromatogram of 5 µg/ml of cefixime standard 124

2.3 Standard curve of cefixime 125

1.1.4

Mean ± SE plasma concentrations (µg/ml) of

cefspan on a semi logarithmic scale versus time

following a single oral administration 400 mg in 10

healthy adult female subjects

132

.24.1




healthy adult male subjects

134

3.1.4



following a single oral administration 400 mg in

136

12

healthy adult female and male subjects

4.1.4


ceforal-3 on a semi logarithmic scale versus time


healthy adult female subjects

138

5.1.4




healthy adult male subjects

140

6.1.4





142

7.1.4


cefspan and ceforal-3 on a semi logarithmic scale

versus time following a single oral administration

400 mg in healthy adult female subjects

144

8.1.4




400 mg in healthy adult male subjects

146

9.1.4




400 mg in healthy adult female and male subjects

148

13

LIST OF TABLES

TABLE NO. TITLE PAGE NO.

.12 Reported values of some pharmacokinetic

parameters of cephalosporins in human beings 6

.22 Different brands of cefixime available in Pakistan 40

.32 Reported values of some bioavailability parameters

of cephalosporins in human beings. 46

3.1

Description of 10 healthy adult female volunteers

involved during investigations of pharmacokinetics

and bioequivalence of cefixime

117

3.2

Description of 10 healthy adult male volunteers

involved during investigations of pharmacokinetics

and bioequivalence of cefixime

118

3.3 Chemicals Used for Analysis of cefixime by HPLC

Method 120

3.4 Definitions and/or formulae of kinetic parameters

derived 126

3.5 Definitions and/or formulae of bioavailability

parameters derived 127

4.1.1

Plasma concentrations (µg/ml) of cefspan following

a single oral administration 400 mg in 10 healthy

adult female subjects

131

4.1.2 Plasma concentrations (µg/ml) of cefspan following


133

14

adult male subjects

4.1.3

Mean ± SE plasma concentrations (µg/ml) of cefspan



135

4.1.4

Plasma concentrations (µg/ml) of ceforal-3 following


adult female subjects

137

4.1.5

Plasma concentrations (µg/ml) of ceforal-3 following


adult male subjects

139

4.1.6

Mean ± SE plasma concentrations (µg/ml) of ceforal-

3 following a single oral administration 400 mg in


141

4.1.7


and ceforal-3 following a single oral administration


143

4.1.8




145

4.1.9




147

4.2.1

Pharmacokinetic parameters of cefspan following a

single oral administration 400 mg in 10 healthy adult

female subjects

151

15

4.2.2

Pharmacokinetic parameters of cefspan following a


male subjects

152

4.2.3

Mean ± SE pharmacokinetic parameters of cefspan



153

4.2.4

Pharmacokinetic parameters of ceforal-3 following a


female subjects

154

4.2.5

Pharmacokinetic parameters of ceforal-3 following a


male subjects

155

4.2.6

Mean ± SE pharmacokinetic parameters of ceforal-3



156

4.2.7




157

4.2.8




158

4.2.9




159

4.3.1 Parameters for bioavailability of cefspan following a

single oral administration 400 mg in 10 adult healthy

163

16

female subjects

4.3.2

Parameters for bioavailability of cefspan following a

single oral administration 400 mg in 10 adult healthy

male subjects

164

4.3.3

Mean ± SE Parameters for bioavailability of cefspan



165

4.3.4

Parameters for bioavailability of ceforal-3 following

a single oral administration 400 mg in 10 adult

healthy female subjects

166

4.3.5

Parameters for bioavailability of ceforal-3 following

a single oral administration 400 mg in 10 adult

healthy male subjects

167

4.3.6

Mean ± SE Parameters for bioavailability of ceforal-

3 following a single oral administration 400 mg in


168

4.3.7

Mean ± SE parameters for bioavailability of cefspan



169

4.3.8




170

4.3.9



400 mg in healthy adult female and male

171

17

4.4.1 Relative bioavailability for AUC and Cmax of ceforal-

3 and cefspan formulations in females 174

4.4.2 Relative bioavailability for AUC and Cmax of ceforal-

3 and cefspan formulations in males 174

LIST OF APPENDICES

APPENDICE

NO. TITLE PAGE NO.

1

Laboratory investigation of 10 healthy female

subjects involved in pharmacokinetic and

bioequivalence study of cefixime

233

2

Laboratory investigation of 10 healthy male

subjects involved in pharmacokinetic and

bioequivalence study of cefixime

253

18

ABSTRACT

In present study pharmacokinetics and bioequivalence of two brands of cefixime i.e.

Cefspan and Ceforal-3 were investigated in adult healthy female and male subjects. Plasma

concentration of Cefixime was determined by HPLC method. Pharmacokinetic parameters were

calculated following one compartment open model. The half life values were found 3.99±0.54 hr

and 3.12±0.39 hr in local adult female subjects and 5.01±0.361 hr and 4.72±0.72 hr in healthy

adult male subjects following administration of Cefspan and Ceforal-3, respectively. The values

of Vd in local adult female and male volunteers were 1.38±0.22 l/kg and 1.10±0.15 l/kg,

respectively, for Cefspan and 1.36±0.17 l/kg and 1.29±0.21 l/kg, respectively, for Ceforal-3. The

values of ClB for Cefspan and Ceforal-3 were 0.27±0.02 l/hr/kg and 0.31±0.02 l/hr/kg,

respectively, in local females and 0.16±0.02 l/hr/kg and 0.21±0.04 l/hr/kg, respectively, in local

males. The values of Cmax were found 2.24±0.23 μg/ml and 2.08±0.16 μg/ml in local adult

female subjects and 2.93±0.24 μg/ml and 2.53±0.31 μg/ml in healthy adult male subjects for

cefspan and ceforal-3, respectively. The values of Tmax were 4.05±0.35 hr and 4.11±0.16 hr for

cefspan and 3.87±0.32 hr and 3.95±0.26 hr for Ceforal-3 after oral administration in local adult

female and male volunteers, respectively. The values of AUC for Cefspan and Ceforal-3 were

27.12±2.25 μg.hr/ml and 23.99±1.07 μg.hr/ml, respectively, in local females and 36.58±3.10

μg.hr/ml and 32.99±5.01 μg.hr/ml, respectively, in local males. In indigenous male and female

human beings, pharmacokinetic and bioavailability parameters of cefixime showed different

values than those reported in literature reflecting environmental and genetic influence.

Pharmacokinetic and bioavailability parameters of cefixime also showed gender variation.

Moreover both brands of cefixime used in present study were found bioequivalent in either

gender.

19

CHAPTER I

INTRODUCTION

The differences of environmental conditions and genetic makeup of man and animals

between drug exporting countries and drug importing countries like Pakistan necessitate the

investigations of pharmacokinetic and bioavailability of drugs in local population as these

differences are manifested through the variation in pharmacokinetic and bioavailability

parameters suggesting different therapeutic dosage regimen to be employed clinically

(Muhammad, 1997; Javed et al., 2006; Javed et al., 2009 a,b; Hussain et al., 2014).

The primary goal of pharmacokinetic is to quantify rate and extent of drug absorption

(bioavailability), distribution and elimination in the intact, living animal or man; and to use this

information to predict the effect of alteration in the dose, dosage regimen, route of administration

and physiologic state on drug accumulation and disposition. Bioequivalence studies are

performed to assess whether two or more than two formulations of the same drug have the

relative rate and extent of absorption. The two brands of same drug can be considered

bioequivalent if their bioavailability i.e. rate and extent of absorption is same. All over the world,

it has become a serious issue that various formulations of the same drug show different

bioavailability therefore cannot be used alternatively. Bioequivalence studies highlight this

difference in the bioavailability and therapeutic efficacy, among formulations of same drug

owing impurities of active ingredients, different types of excepients, manufacturing faults as the

insufficiency of mixing procedure, coating protocol and granulation method (Esimone et al.,

2008; Maggio et al., 2008; Fujii et al., 2009). Further, lowering of health care costs may

tremendously increase the use of generic drug product. Market is flooded with national as well as

multinational drug products amongst which physicians must select therapeutic equivalents

(Miller and Storm, 1990; Foster, 1991). So, the need of bioavailability and bioequivalence

studies and clinical trials has been increased for local population, before marketing the drugs that

has been repeatedly emphasized by clinicians and health ministry (Vogel and Motulsky, 1986;

Haq, 1997).

20

Antibiotics play an important role in the treatment of various infectious diseases in men and

domestic animals. In treating microbial infection, it is essential that an effective concentration of an

antibacterial drug be rapidly attained at the focus of infection and maintained for an adequate time.

The concentration achieved varies with systemic availability of the drug based on its

physicochemical characteristics, dosage form, dosing rate, routes of administration and ability to

gain access to the infection site, subsequently influencing the bioavailability and pharmacokinetic of

the drug (Javed, 1998). Cefixime is a semi-synthetic, 3rd generation and orally acting

cephalosporin and it is well stable to inactivation by beta-lactamase enzymes (Baltimore, 2005).

It is effective against different human ailments including otitis media, gonorrhea, typhoid and

certain respiratory and urinary tract infections. Cefixime is a bactericidal drug causing its action

by inhibiting synthesis of the bacterial cell wall (Memon et al., 1997). Although, several studies

have been reported on the pharmacokinetics of cefixime (Evene et al., 2001; Ying et al., 2003;

Asiri et al., 2005; Zakeri et al., 2008), still the availability of literature on disposition kinetics

and bioavailability in local population of Pakistan especially with reference to gender variations

have been found to an limited extent.

Keeping in view the facts in preceding lines, present project was designed to investigate

pharmacokinetics and bioequivalence of two broadly used brands of cefixime in clinical

practices i.e. a multinational brand cefspan (Barrett Hodgson (Pvt.) Ltd. Karachi, Pakistan) and a

local brand ceforal-3 (Zafa Pharmaceuticals Laboratories (Pvt.) Ltd. Karachi, Pakistan) in

healthy adult female and male subjects. Thus the project encompassed a comparison of two

drugs in respect of brand dependent and gender dependant disposition kinetics and

bioavailability in female and male subjects.

21

CHAPTER II

REVIEW OF LITERATURE

2.1 Cephalosporins:

Cephalosporins are beta-lactam antibiotics derived in 1948 by Brotzu from the fungus

"Cephalosporium acremonium" from the sea near a sewer outlet on the Sardinian coast. Crude

filtrates from cultures of this fungus inhibited the growth or Staph. aureus In-vitro and cured

staphylococcal infections and also treated typhoid fever in man (Goodman and Gilman’s, 1996).

2.1.1 Mechanism of action of antibiotics:

Way the antibiotics act and produce their effects on the microbes have been categorized

mainly into four types; inhibition of synthesis of microbial cell wall, inhibition of bacterial cell

membrane synthesis, inhibition of the synthesis of nucleic acid and inhibition of protein

synthesis (Prescott and Baggot, 1988).

2.1.2 Mode of action of cephalosporin:

Cell wall of bacteria is important for supporting the underlying plasma membrane against

internal osmotic pressure and prevents penetration of antibacterial agents. It also prevents easy

access of lysozyme (an enzyme, which can destroy cell wall structures and is found in white

blood cells and tissue fluids) to the cell wall that contains peptidoglycan. About 30 bacterial

enzymes involves in the biosynthesis of peptidoglycan. The last step of peptidoglycan synthesis

is transpeptidation reaction, which is inhibited by beta-lactam antibiotics, results in inhibition of

bacterial cell wall synthesis (Tomasz, 1986).

Cephalosporins attach to the bacterial cell wall through penicillin-binding proteins

(PBPs). These proteins are under chromosomal control; therefore mutation may alter their

number and affinities for specific beta-lactam drugs (Neu, 1988). In addition cephalosporins

probably also participates in removal or inactivation of an inhibitor of autolytic enzymes

(hydrolysis) of bacterial cell walls. The activation of these autolytic enzymes results in the lyses

of cell wall and ultimately bacterial death (Tomasz, 1986).

22

2.1.2.1 Penicillin binding proteins:

Penicillin Binding Proteins (PBPs)

An important step, transpeptidase reaction, in bacterial cell wall synthesis is catalyzed by

Penicillin-binding Proteins (PBPs). In this step a terminal alanine is removed in a cross

linking reaction with a nearby peptide.

Antibacterial action of cephalosporin occurs through binding to these proteins and

resulting in inhibition of activity of these proteins.

Resistance to ß-lactams is developed in bacteria due to alteration of PBPs (penicillin-

binding proteins) [Chambers et al., 1998].

2.1.2.2 Development of antibiotic resistance:

Resistance may be acquired to beta-lactam antibiotics either by developing new PBP

genes or by mutation within existing genes of PBPs (e.g. staphylococcal resistance to

methicillin) or by acquiring new "pieces" of PBP genes (e.g. pneumococcal, gonococcal and

meningococcal resistance) [Chambers et al., 1998].

Resistance to ß-lactams:

There are several mechanisms of development of bacterial resistance to ß-Lactams and

elaboration of the enzyme ß-lactamase is most important among these. This enzyme

hydrolyzes the ß-lactam ring. Genes for ß-lactamase may be present in both bacteria

(Gram-positive and Gram-negative). Some inhibitors for this enzyme such as sulbactum

and clavulanic acid can minimize this resistance by binding to some ß-lactamases.

Alteration of PBPs is a second mechanism for bacterial resistance development.It may

occur either by mutation of the existing genes or by acquiring new genes or pieces of

genes, as described earlier.

A 3rd mechanism which is seen in Gram -ve bacteria is due to alteration of genes

specifying the porins (outer membrane proteins) and thus reducing the permeability of β -

lactams (e.g. resistance of Enterbacteriaceaeto some cephalosporins and that of

Pseudomonas spp. to ureidopenicillins).

Same bacterial cells may show multiple resistance mechanisms (Archer and Polk, 1998).

23

2.1.3 Classification and antibacterial spectrum of cephalosporin:

Cephalosporin may be classified by their spectrum of antimicrobial activity into four

generations namely first, second, third and fourth generation (Karchmer, 1995). Third-generation

cephalosporin drugs (such as ceftriaxone and cefixime) possess broader spectrum of activity

against the Gram-negative bacilli than agents of 1st or 2nd generation, but are less effective

against Gram +ve cocci as compare to earlier generation drugs. However, these are active against

beta-lactamase producingNeisseria species and H. influenza (Donowitz and Mandell, 1988).

2.1.4 Pharmacokinetics of cephalosporin:

Pharmacokientic parameters of cephalosporins in human being and in animals have been

presented in Table 2.1.

2.1.4.1 Absorption:

Some cephalosporin such as cefixime, cefadroxil, cepharadine, cephalexin and cefaclor

are well absorbed from the intestinal tract. Therefore, they can be given orally. Other

cephalosporins such as ceftriaxone is poorly absorbed through the intestinal tract, thus it is

administered parenterally.

2.1.4.2 Distribution:

Cephalosporins distribute widely throughout the body. They can easily penetrate into

pleural, pericardial, CSF, placenta and joint fluids. In addition, cephalosporins reach high

concentration in skin, muscles, stomach wall, liver, spleen and kidney. The Vd of cephalosporins

ranges born 0.l to 0.4 L and their degree of plasma protein binding ranges from 17% to 90%.

Cephalosporins are not extensively bio-transformed, but are distributed and excreted in active

form.

2.1.4.3 Excretion:

Cephalosporins are mainly eliminated via the kidney. However, about 20% of a given

dose of cefixime is excreted via urine in unchanged form while remainder (80%) is excreted

throughbile (Klepser et al., 1995).

24

Table 2.1: Reported values of some pharmacokinetic parameters of cephalosporins in human beings.

Cephalosporin Subjects

Dose

Route

Pharmacokinetic parameters

Reference

mg

mg

per

kg

B β 1/2t dV BCl

µg/ml hr-1 hr L/kg L/hr/kg

Cephalexin Cats - 10

IV

- 0.42 1.68 0.33 0.02

Albarellos et al.,

2011

Cefepime

Cystic

fibrosis

patients - - - - - - 0.32 -

Ambrose et al.,

2002

Cefepime

Patients with

LRTIs - - - - - - 0.22 -

Ambrose et al.,

2002

Cefepime Sepsis - - - - - - 0.47 -

Ambrose et al.,

2002

Cefepime Young - - - - - - 0.21 -

Ambrose et al.,

2002

Cefepime Elders - - - - - - 0.23 -

Ambrose et al.,

2002

Cefixime

Healthy

male

200

mg/10ml - Oral - - 2.23 - -

Asiri et al.,

2005

25

Cefixime -

200

mg/10ml -

Oral - - 3.32 - -

Asiri et al.,

2005

Cefixime - 200 - Oral Tablet - - 3 - - Baltimore, 2005

Cefixime Young

400 mg

OD for 5

days - - - - 3.5 - - Baltimore, 2005

Cefixime Elderly

400 mg

OD for 5

days - - - - 4.2 - - Baltimore, 2005

Cefepime - 500 -

IV

- - 1.9 - -

Barbhaiya et al.,

1990c

Cefepime

Human

subjects 250 -

IV

- - 1.8 - -

Barbhaiya et al.,

1990c

Cefepime - 1000 -

IV

- - 1.9 - -

Barbhaiya et al.,

1990c

Cefprozil

Beagle dogs 125

IV

- - 80 - -

Barbhayia et al.,

1992a

Cefprozil

Beagle dogs 125 Oral - - 104 - -

Barbhayia et al.,

1992a

Cefepime

Young

males 1000

IV

- - 2.26 0.21 0.0924

Barbhaiya et al.,

1992b

Cefepime Young - - IV - - 2.15 0.21 0.0936 Barbhaiya et al.,

26

females 1992b

Cefepime

Elderly

males - -

IV

- - 3.05 0.23 0.0666

Barbhaiya et al.,

1992b

Cefepime

Elder

Females - -

IV

- - 2.92 0.24 0.0732

Barbhaiya et al.,

1992b

Cefaclor Fasting 250 - Oral - - 1.17 - -

Barbhayia et al.,

1990

Cefaclor Fasting 250 - Oral - - 1.16 - -

Barbhayia et al.,

1990

Cefprozil With food 250 - Oral - - 0.83 - -

Barbhayia et al.,

1990

Cefprozil With food 250 - Oral - - 0.86 - -

Barbhayia et al.,

1990

Cefprozil

Healthy

male

volunteers 250 Oral - - 1.4 - -

Barbhayia et al.,

1990a

Cefaclor

Healthy

male

volunteers 250 - Oral - - 0.5 - -

Barbhayia et al.,

1990a

Cefprozil

Healthy

male


Barbhayia et al.,

1990a

27

Cefaclor

Healthy

male


Barbhayia et al.,

1990a

Cefprozil Humen 250 Oral - - 1.28 - -

Barbhayia et al.,

1990b

Cefprozil

- 500 Oral - - 1.29 - -

Barbhayia et al.,

1990b

Cefprozil

- 1000 Oral - - 1.27 - -

Barbhayia et al.,

1990b

Cefotetan - - - - - - 4.4 - - Bergan, 1987

Cefonicid - - - - - - 5 - - Bergan, 1987

Cefpiramide - - - - - - 3.5 - - Bergan, 1987

Ceftriaxone - - - - - - 8.5 - - Bergan, 1987

Cefixime Dogs - 6.25

IV

- - 6.4 2.2 0.24

Bialer et al.,

1987

Cefixime Dogs - 25

IV

- - 6.4 2.8 0.312

Bialer et al.,

1987

Cefpodoxime

Healthy

adult 100-400 Oral - -

1.9-

2.8 - - Borin, 1991

Cefoperazone Neonates - 50 - - - 5.5 0.12 0.6

Bosso et al.,

1983

Ceftriaxone Healthy 2000 IV - - 6.2 11.7 1.30 Bourget et al.,

28

volunteers 1993

Ceftriaxone

Pregnant

women 2000 Infusion - - 6.77 12.54 1.28

Bourget et al.,

1993

Cefixime

Normal

subjects 50 - - - - 3 0.1 0.4

Brittain et al.,

1985

Cefixime - 100 - - - - 3 0.1 0.4

Brittain et al.,

1985

Cefixime - 200 - - - - 3 0.1 0.4

Brittain et al.,

1985

Cefixime - 400 - - - - 3 0.1 0.4

Brittain et al.,

1985

Cefixime

Healthy

subjects 200 - - - - 3 - -

Brogden and

Campoli-

Richards, 1989

Cefepime Neonates - 50 - - - 4.9 0.43 1.1

Capparelli et al.,

2005

Cefoperazone Calves - - - - - 0.9 - -

Carli et al.,

1986

Cefoperazone

In women

after

postpartum 1000

IV

- - 1.35 10.51 5.38

Charles and

Bryan, 1986

Cefotaxime 1000 IV - - 1.32 58.17 31.2 Charles and

29

Bryan, 1986

Cefpodoxime

Healthy

adult 400 - Oral - - 3.5 - 5.40

Chugh and

Agrawal, 2003

Ceftazidime

Male

without

mechanical

ventilation - - - - - 1.81 22.8 7.2

Connil et al.,

2007

Ceftazidime

Female

without

mechanical

ventilation - - - - - 1.98 28.1 6.6

Connil et al.,

2007

Ceftazidime

Male with

mechanical

ventilation - - - - - 2.15 31.6 6.1

Connil et al.,

2007

Ceftazidime

Female with

mechanical

ventilation - - - - - 2.17 49.4 5.7

Connil et al.,

2007

Ceftolozane

Neutropenic

mice 25 - - - 11.6 - -

Craig and

Andes, 2007

Ceftolozane - 100 - - - 13.8 - -

Craig and

Andes, 2007

Ceftolozane - 400 - - - 14.1 - - Craig and

30

Andes, 2007

Cefoperazone

Healthy

male and

female adult 2000 -

IV

- - 10.3 1.1 1.782

Deeter et al.,

1990

Cefotaxime

- 2000 -

IV

- - 20 10.2 10.34

Deeter et al.,

1990

Ceftriaxone

- 2000 -

IV

- - 15.2 6.2 6.48

Deeter et al.,

1990

Ceftazidine

- 2000 -

IV

- - 3.7 9.4 4.76

Deeter et al.,

1990

Ceftizoxime

- 2000 -

IV

- - 3.5 7.9 3.75

Deeter et al.,

1990

Cefazolin Neonates - 30 - - - - 0.28 0.8

Deguchi et al.,

1988

Cefixime

Normal

subjects 200 - Oral - - 3.73 - 11.64

Dhib et al.,

1991

Cefixime

Uremic

patients 200 - Oral - -

12 to

14 - -

Dhib et al.,

1991

Ceftazidime

Healthy

adult 2000 - - - - 1.75 0.21 6.4

Drusano et al.,

1984

Cefixime - 200 - Oral - - 3.4 17 3.55

Duverene et al.,

1992

31

Cefixime - 200 -

IV

- - 3.3 17 -

Duverene et al.,

1992

Cefixime Sheep - - - - - - 4.67 62.48

Eldalo et al.,

2004

Cefazolin

In

parturients

undergoing

cesarean

surgery 2000 - - - 0.34 - 9.44 7.18

Elkomy et al.,

2014

Cefixime

Healthy

male

subjects - - - - -

3.0to4

.0 - -

Faulkner et al.,

1987

Cefixime

Healthy

volunteers 200 -

Solution

IV - -

3.5

3.2to - -

Faulkner et al.,

1988

Cefixime

Healthy

volunteers 200 -

Oral

solution - -

3.5

3.2to - -

Faulkner et al.,

1988

Cefixime

Healthy

volunteers 200 -

Oral

capsule - -

3.5

3.2to - -

Faulkner et al.,

1988

Cefixime

Healthy

volunteers 400 -

Oral

capsule - -

3.5

3.2to - -

Faulkner et al.,

1988

Cephalexin Calves - - - - - 2 0.3 1.9

Garg et al.,

1992

32

Ceftriaxone

Calves

(buffalo) - 10

IV

- - 1.3 0.5 0.264

Gohil et al.,

2009

Ceftriaxone

Calves

(buffalo) - 10 IM - - 4.4 1.5 0.24

Gohil et al.,

2009

Cefoperazone

Parturients

in immediate

postpartum

period after

cesarean

section 2000 -

IV

- - 2.53 0.18 0.066

Gonik et al.,

1986

Ceftazidime

Female

dromedary

camels -

10

IV

- - 2.85 - -

Goudah and

Sherifa, 2013

Ceftazidime - -

10

IM - - 3.2 - -

Goudah and

Sherifa, 2013

Cefepime

Healthy

rabbits - - IM - - 3.85 - -

Goudah et al.,

2006

Cefepime

Febrile

rabbits - - IM - - 3.01 - -

Goudah et al.,

2006

Cefotaxime Neonates - 25 - - - 3.7 0.43 1.57

Gouyon et al.,

1990

Cefixime Healthy 400 - Oral - - 3.2 1.1 8.46 Guay et al.,

33

subjects 1986

Ceftriaxone Sheep - - - - - - 0.3 3.7

Guerrini et al.,

1985

Cefoperazone Sheep - 47

IV

- - - 0.2 2.7

Guerrini et al.,

1985

Cefoperazone

Cross bred

calves - 4

IV

5.44 - 2.05 1.11 -

Gupta et al.,

2007

Cefoperazone

Cross bred

calves - 20 IM 5.28

0.30

1 2.31 2.95 1.28

Gupta et al.,

2008

Cefixime

Pregnant and

lactating rats - 17.8

IV

Infusion - - 6.9 - -

Halperinwalega

et al., 1988

Cefixime

Healthy

adult male 400 Oral - - 2.6 - 27

Healy et al.,

1989

Cefuroxime

Malnourishe

d rats

-

2.2 Oral - - 37 - -

Hernandez et

al., 2008

Cefuroxime

Controlled

rats

-

2.2 Oral - - 37.6 - -

Hernandez et

al., 2008

Cefepime

Febrile

buffalo

calves - 10

IV

19.6

0.23

4 3 0.48 0.0988

Joshi and

Suresh, 2009

Cephalexin

Healthy

adult 1000 - Oral - -

0.5-

1.2 ˂3 -

Kalman and

Steven, 1990

34

Cefadroxil

Healthy

adult - - Oral - -

1.1-

2.0 - -

Kalman and

Steven, 1990

Cephradine

Healthy


0.7-

2.0

9.65-

15.4 -

Kalman and

Steven, 1990

Cephalothin

Healthy

adult 1000 -

Parenteral-

IV - -

0.5-

1.0

5.0-

14.0 -

Kalman and

Steven, 1990

Cephapirin

Healthy

adult 1000 -

Parenteral-

IV - -

0.3-

0.5 8.8 -

Kalman and

Steven, 1990

Cefazolin

Healthy

adult 1000 - Parenteral - -

1.2-

2.2 7.0-9.0 -

Kalman and

Steven, 1990

Cefuroxime

Healthy


1.0-

2.0 - -

Kalman and

Steven, 1990

Cefuroxime

Healthy


1.0-

2.0 - -

Kalman and

Steven, 1990

Cefamandole

Healthy


0.5-

2.1 - -

Kalman and

Steven, 1990

Cefoxitin

Healthy


0.7-

1.1 - -

Kalman and

Steven, 1990

Cefmetazole

Healthy

adult 1000 - Parenteral - - 1 - -

Kalman and

Steven, 1990

Cefotetan

Healthy


2.8-

4.6 - -

Kalman and

Steven, 1990

35

Cefaclor

Healthy

adult - - Oral - -

0.5-

1.0 - -

Kalman and

Steven, 1990

Cefdinir

Healthy


1.5-

2.0 - -

Kalman and

Steven, 1990

Cefoperazone

Healthy

adult 1000 -

IV

- -

1.6-

2.6 - 15-30

Kalman and

Steven, 1990

Cefotaxime

Healthy

adult 1000 -

IV

- -

0.9-

1.7 - -

Kalman and

Steven, 1990

Ceftizoxime

Healthy

adult 1000 -

IV

- -

1.4-

1.9 - 28-31

Kalman and

Steven, 1990

Ceftriaxone

Healthy

adult 1000 -

IV

- -

5.4-

10.9 - -

Kalman and

Steven, 1990

Ceftazidime

Healthy

adult - - Parenteral - -

1.4-

2.0 - 80-90

Kalman and

Steven, 1990

Cefixime

Healthy


3.0-

4.0 - 18

Kalman and

Steven, 1990

Cefroxadine

Healthy

adult - - - - - 1 - -

Kang et al.,

2006

Cefadroxil

Healthy

adult 500 - - - - 1.5 - 1.8

Kano et al.,

2008

Cefuroxime

Healthy


Kaza et al.,

2012

36

Cefuroxime

Healthy


Kaza et al.,

2012

Cefixime

Healthy

male and

female

volunteers 200 - Oral Tablet - - 2.91 - -

Kees et al.,

1990

Cefixime - 200 - Oral syrup - - 3.13 - -

Kees et al.,

1990

Cefixime - 200 -

Oral

suspension - - 3.01 - -

Kees et al.,

1990

Cefixime

Healthy

volunteers 200 - Oral Tablet - -

2.9-

3.1 - -

Kees et al.,

1990 and Kees

and Naber, 1990

Cefixime - 200 - Oral syrup - -

2.9-

3.1 - -

Kees et al.,

1990 and Kees

and Naber, 1990

Cefixime - 200 -

Oral

suspension - -

2.9-

3.1 - -

Kees et al.,

1990 and Kees

and Naber, 1990

Cefixime

Healthy

male 200 - Oral Tablet - - 4.98 - -

Lan-Ying et al.,

2004

Cefixime - 200 - Oral - - 5.28 - - Lan-Ying et al.,

37

Capsule 2004

Cefixime - - - - - - 3 - -

Legget et al.,

1990

Cefaclor

Female

subjects 500

Oral

withwater - - 0.59 - - Li et al., 2009

Cefaclor

Female

subjects 500

Oral

withjuice - - 0.62 - - Li et al., 2009

Cefpodoxime - 400 - Oral - - 2.6 - - Liu et al., 2005

Cefixime - 400 - Oral - - 4 - - Liu et al., 2005

Cefixime Chinese men 400 - - - - 4.2 - - Liu et al., 2007

Ceftobiprote

500 -

IV

- 5.18 - 7.65 0.51

Lodise et al.,

2007

Cefixime - - - - - - 3 - - Low, 1995

Cefixime

Renal

patients 100 - - - - 4.2 - -

Maeda et al.,

1986

Ceftriaxone

Calves

(cow) - 10

IV

- - 1.6 0.4 3.2

Maradiya et al.,

2010

Ceftriaxone

Calves

(cow) - 10 IM - - 5 1.2 2.7

Maradiya et al.,

2010

Ceftriaxone

Cardiac

patients 1000 -

IV

- - 8.1 18.3 23.2

Martin et al.,

1996

Cefepime Mice - 80 - - - 0.38 - 16.7 Mathe et al.,

38

2006

Ceftriaxone

Healthy

adult 1000 - IM - -

5.0-

9.0 - -

Meyers et al.,

1983

Ceftolozane

Females and

males 500 - - - - 2.48 11.8 5.18

Miller et al.,

2012

Cefixime - 200 - Oral - - 3.15 - -

Min-Ji et al.,

2004

Cefixime - 200 - Oral - - 3.31 - -

Min-Ji et al.,

2004

Cephalexin

Healthy

male and

female

volunteers 500 - - - - 1.06 25.13 13.21

Mircioiu et al.,

2007

Cephalexin

Healthy

volunteers 500 - - - 0.72 0.98 21.68 15.34

Mohamed et al.,

2011

Cephalexin

Healthy

volunteers 500 - - - 0.73 0.99 20.96 14.81

Mohamed et al.,

2011

Cephalexin

Healthy

volunteers 500 - - - 0.73 0.98 24.64 17.81

Mohamed et al.,

2011

Cefixime

Healthy

male


Montay et al.,

1989

39

Cefixime

Healthy

male


Montay et al.,

1991

Cefixime

Patients

undergoing

cholecystect

omy

2200 x

mg/day

- - - - 3 - -

Moorthi et al.,

1990

Cefixime Children - 1.5 - - - 2.7 - -

Motohiro et al.,

1986

Cefixime Children - 3 - - - 2.8 - -

Motohiro et al.,

1986

Cefixime - 50 -

Oral

granules - - 3.09 - -

Motohiro et al.,

1986

Cefixime - 50 -

Oral

capsule - - 2.87 - -

Motohiro et al.,

1986

Ceftriaxone Neonates - 50 - - - 15.4 0.33 0.28

Mulhall et al.,

1985

Cefixime

Healthy

volunteers 50 mg bid - - - - 2.5 - -

Nakashima et

al., 1987

Cefixime

Healthy

volunteers

100 mg

bid - - - - 2.4 - -

Nakashima et

al., 1987

Cefixime Healthy 200 mg - - - 2.3 - - Nakashima et

40

volunteers bid al., 1987

Cefixime - 200 - - - - 2.5 - - Nies, 1989

Ceftriaxone Humen

Water

asdiluent - IM - 0.1 7.1 9.37 0.904

Patel et al.,

1982

Ceftriaxone -

Lidocain

asdiluent - IM - 0.1 7 9.22 0.890

Patel et al.,

1982

Ceftriaxone

Young

subjects 1000 -

IV

-

0.09

3 7.5 11 -

Patel et al.,

1984

Ceftriaxone

Adult

subjects 1000 -

IV

-

0.07

8 8.9 10.7 -

Patel et al.,

1984

Cefepime Calves - 5

IV

- - 3.7 0.43 1.81

Patel et al.,

2006

Cefepime

Cow

(calves) - 5

IV

- - 3.7 0.6 1.8

Patel et al.,

2006

Cefepime

Cow

(calves) - 5 IM - - 6.7 1 1.7

Patel et al.,

2006

Cefepime Sheep - 20

IV

- - 2.5 0.4 2.5

Patel et al.,

2010

Cefepime Sheep - 20 IM - - 5.2 1.1 0.2

Patel et al.,

2010

Cefepime Goat - 10

IV

- - 2.7 0.5 2.2

Patni et al.,

2008

41

Cefepime Goat - 10 IM - - 4.9 - 1.3

Patni et al.,

2008

Cefpodoxime

Male /

female sub

jects 200 - Oral -

0.12

4 5.9 - -

Peter et al.,

1992

Ceftriaxone

Males and

females 2000 -

IV

- - 7.5 11.7 1.284

Pletz et al.,

2004

Cephapirin

Cow

(lactating) - - - - - - - 13

Prades et al.,

1988

Cefpirome

Buffalo

calves - 10 IM 9.23 0.29 2.39 0.42 0.12

Rajput et al.,

2007

Cefpirome

Crossbred

calves - 10 IM 12 0.34 - - -

Rajput et al.,

2012

Ceftizoxime Neonates - 5-25 - - - 7.2 0.37 0.68

Reed et al.,

1991

Cefoxitin Neonates - 30 - - - 1.43 0.5 4.5

Regazzi et al.,

1983

Cefuroxime Neonates - 10 - - - 4.6 - -

Renlund and

Pettay, 1977

Ceftriaxone

Male and

female

adults 250 -

IV

- - 8.16 - -

Robert et al.,

2001

42

Ceftriaxone - 250 - IM - - 7.6 - -

Robert et al.,

2001

Cefixime - 400 -

Oral

- - 3.61 - -

Robert et al.,

2001

Ceftazidime Sheep - - - - - 1.6 0.4 - Rule et al., 1991

(Bioximet)

Cefuroxime

Healthy

volunteers 500 - Oral -

0.61

3 1.169 - -

Sabati et al.,

2014

(Zinnat)

Cefuroxime

Healthy

volunteers 500 - Oral -

0.63

2 1.142 - -

Sabati et al.,

2014

Cefixime - - - - - - 3 - - Saito, 1985

Cefotaxime

Bufalo

calves - 13 - 5.76 0.54 1.31 1.34 713.6

Sharma and

Anil, 2003

Cefotaxime

Bufalo

calves - 10

SC

6.33

0.39

2 1.77 1.17 0.45

Sharma and

Anil., 2006

Ceftazidime

Febrile

buffalo

calves - 10

IV

31.04 0.19 3.73 0.2 47.9

Sharma and

Shah, 2012

Cefotaxime

Febrile

buffalo

calves - 10

IV

1.84

0.38

1 1.85 1.7 644

Sharma et al.,

2006

Cephradine

Healthy

adult male 250 - PO

2.79

mg/ml 1.74 0.44 9.65 15.4

Shoaib et al.,

2008

43

Cefixime

Healthy

volunteers 200 - Oral Tablet - - 2.9 - -

Shu-Ying et al.,

2009

Cefixime - 200 -

Oral

capsule - - 2.7 - -

Shu-Ying et al.,

2009

(Cis-isomer)

Cefprozil

Lactating

females - - - - 1.69 - 0.164

Shyu et al.,

1992

(Trans-isomer)

Cefprozil - - - - - - 1.35 - 0.161

Shyu et al.,

1992

Cefazolin Calves - - - - - 0.6 0.2 5.8

Soback et al.,

1987

Cefoxitin Calves - - - - - 1.1 - - Soback, 1988

Ceftazidime Male 1000 -

IV

- - 1.58 13.33 6.99

Sommers et al.,

1983

Ceftazidime Female 1000 -

IV

- - 1.5 11.05 5.82

Sommers et al.,

1983

Ceftazidime

Male 1000 - IM - - 1.83 22.09 28.9

Sommers et al.,

1983

Ceftazidime Female 1000 - IM - - 1.89 16.17 37.2

Sommers et al.,

1983

Cefoperazone

Healthy

Adult 1000 -

IV

- - 2.6 - -

Sootornpas et

al., 2011

Ceftazidime Juvenile - 20 IV - 0.03 20.6 - - Stamper et al.,

44

loggerhead

sea turtles

1999

Ceftazidime

- -

20

IM - 0.04 19.1 - -

Stamper et al.,

1999

Cefoperazone

Healthy

Adult - - - - - 1.87 0.14 4.04

Standiford et al.,

1982

Cefotaxime

Healthy

Adult - - - - - 1.18 0.23 14.04

Standiford et al.,

1982

Cefixime

Healthy

male

volunteers 400 - - - - 3.8 - -

Stone et al.,

1988

Ceftriaxone Sheep - 10

IV

- - 1.2 0.4 3.9

Swati et al.,

2010

Ceftriaxone Sheep - 10 IM - - 2.2 0.4 2.2

Swati et al.,

2010

Ceftifur Healthy pigs - -

IV

- - 21 0.527 0.017

Tantituvanont et

al., 2009

Ceftriaxone Goat - 20

IV

- - 1.5 0.6 4.5

Tiwari et al.,

2009

Ceftriaxone Goat - 20 IM - - 2 0.5 3

Tiwari et al.,

2009

Ceftriaxone Transplant 2000 - IV - 0.05 13.1 - - Toth et al., 1991

45

recepients 3

Ceftriaxone

Normal

subjects 2000 -

IV

- - 5.8 - - Toth et al., 1991

Ceftizoxime

Female

andmale

subjects 2000 -

IV

- - 2.04 0.34 0.166

Valle and Marc,

1991

Cefotaxime - 2000 -

IV

- - 1.43 0.28 0.229

Valle and Marc,

1991

Ceftazidime Neonates - 25 - - - 8.15 0.32 0.46

VandenAnker et

al., 1995

Cefixime

Patients of

T-tube

drainage - - - - - 3.5 - 11.7

Westphal et al.,

1992

Cefixime

Patients with

RTIs (M&F) 200 - - - 0.22 3.09 0.15 0.0324 Yi et al., 1995

Cefuroxime

sodium

Beagle

Dogs - 40

IV

- - 1.21 0.61 0.34

Zhao et al.,

2012

Cefuroxime

lysine - - -

IV

- - 0.91 0.42 0.31

Zhao et al.,

2012

Ceftriaxone

Males and

females 1000 - IM - - 8.2 - -

Zhou et al.,

1985

Ceftriaxone - 1000 - IV - - 8.1 8.5 - Zhou et al.,

46

1985

Cefixime - - -

Oral and

IV - -

3.5to4

.0 0.3 - Ziv et al., 1995

LRTIs = Lower Respiratory Tract Infections PO = Per Oral OD = Once Daily

IV = Intra Venous IM = Intra Muscular SC = Sub Cutaneous

47

2.1.5 Route of administration of cephalosporin and dosage regimens:

β-lactams have time-dependent killing activity against infectious organisms. To achieve

their optimal effect the concentration of drug in serum must be above minimum inhibitory

concentration. Therefore, dosing frequency at right time is essential (Walker et al., 2012).

Cephalosporins may be given orally, intramuscularly and intravenously depending on the

specific agent and therapeutic indications. The daily oral dose of cephalosporins ranges from 5 to

50 mg/Kg and this amount is usually divided into 2-4 equal doses. The parenteral dose is 50-200

mg/Kg and this amount is also divided into 2-6 equal doses depending on the half-life of

individual drugs.

2.1.6 Therapeutic uses of cephalosporin:

It was reported that cephalosporins are effective as therapeutic as well as prophylactic

drugs. Thus, these are considered the drug of choice for the serious infections caused by

Entrobacter, Klebsiella, Serratia, Hemophillus species and Proteus providencia. Ceftriaxone and

cefixime are the drugs of choice now to treat typhoid and meningitis in children and adults

(Donowtiz and Mandell 1988).

2.1.7 Adverse reactions of cephalosporin:

Hypersensitivity reactions including rash, fever, eosinophlia, serum sickness and

anaphylaxis are the most common side effects of cephalosporins (Petz, 1978). It was found that

the incidence of allergic reactions to the cephalosporins increased in penicillin sensitive patients

and it may due to their similar structures (Bennett et al., 1983) and enhanced nephrotoxicity of

aminoglycoside antibiotics by cephalosporins was also reported (Barza, 1978).

Prothrombin activity may be reduced by cephalosporins. Those who are at risk include

the patients of liver or kidney dysfunctions, patients who previously have been stabilized on

anticoagulants, as well as the patients who have received the protracted course of antibacterial

drugs and persons having poor nutritional state. Patients at risk should be monitored for

prothrombin time and as an indication exogenous vitamin K should be administered (Baltimore,

2005).

48

2.1.8 Cephalosporin in typhoid:

Treatment of Typhoid treatment with the existing popular antibiotic drugs in the recent

years has not been satisfactory and this may be due to that the strain of Salmonella typhi has got

emergent resistance all over the world including Pakistan. Ceftriaxone, cefixime and other third

generation cephalosporins have emerged as good and satisfactory alternatives to previous oral

drugs used for typhoid fever. Previous studies in children with MDR typhoid fever have shown

more than 90% successful cure rate with parenteral ceftriaxone in Pakistan (Naqvi et al., 1992).

Typhoid fever is a complicated, severe and prolonged disease produced by Salmonella

typhi (Gram-negative bacilli) through contaminated food or water intake. Typhoid fever has

incubation period of usually 10- 14 days but may vary from 7-21 days depending on the number

of ingested organisms (Homick et al., 1970).

Recently, the incidence of typhoid fever infection has increased considerably and there

are more than five million cases of typhoid fever worldwide yearly reported by the World Health

Organization (Edelman and Levin, 1986). Typhoid fever is a major cause of mortality and

morbidity in developing countries (Taylor et al., 1983) including Pakistan (Rathore et al., 1996;

Abdulbaqi and Rab, 1996).

For treating the typhoid fever, a large number of antibiotics are used such as ampicillin,

chloramphenicol and trimethoprim-sulphamethoxazole. These drugs have been the therapy of

choice for enteric fever. A marked increase in resistant strains of Salmonella typhi have been

reported showing resistance to ampicillin, chloramphenicol and trimethoprim-sulphamethoxazole

around the world (Rowe et al., 1990) including Pakistan (Bhutta et al., 1994; Rathore et al.,

1996). The ineffectiveness of these drugs in treatment of typhoid fever is not fully understood

but it may be due to insufficient penetration of the drug into the infected cell or poor anti-

bactericidal action of antibiotics (Abdulbaqi and Rab 1996).

Outbreak of multidrug-resistant (MDR) Salmonella typhi is a major problem related to

public health. The first serious problem of MDR Salmonella typhi to chloramphenicol was

reported in Mexico in 1972. Thereafter, the MDR Salmonella typhi strains resistant to

chloramphenicol were reported in Vietnam (Butler et al., 1993), Bangladesh (Samadi, 1982),

India (Chandra et al., 1984) and Pakistan (Rathore et al., 1996). Although oral quinolones offer

49

an effective and safe drug alternative for treatment of MDR typhoid fever in adults (Bryan et al.,

1986), there are still major concerns in children about its adverse effects (Lumbiganon et al.,

1991; Navolekar et al., 1992). Thus, new inexpensive effective antibiotics with less duration of

therapy are needed because of alarming spread of resistant strains of the Salmonella typhi

throughout the world.

Recently, third generation cephalosporins have proved a satisfactory substitutes to

previous oral therapies for typhoid fever. Response to these drugs can be changed by many

factors including age and complications occurring simultaneously with typhoid fever (fever,

illness, liver dysfunction, renal dysfunction and malnutrition).

2.1.9 Cephalosporin in gonorrhea:

As antibiotic resistance is a big problem of today. Because of penicillin and tetracycline

resistance development in Neisseria gonorrheae, ceftriaxone is recommended now a day to treat

gonorrhea. However an oral alternative to parenteral ceftriaxone is needed. Cefixime, an oral

cephalosporin is also effective against resistant strains of gonococciand it has suitable

pharmacokinetics for single dose/day administration. Cefixime 400-800 mg orally given as once

a day is sufficient and effective as same as 250 mg dosage regimn of IM ceftriaxone for treating

uncomplicated gonorrhea (Handsfield et al., 1991).

2.2 Drug profile of cefixime:

Cefixime is a 3rd generation cephalosporin, which is active orally. It is a cell wall

synthesis inhibitor (Adam et al., 1995; Memon et al., 1997).

Cefixime has potent antibacterial activity with long duration of action and is well stable to beta -

lactamase (Arshad et al., 2009). Cefixime treats various infections which are caused by different

Gram +ve and Gram -ve microorganisms.It may be indicated in otitis media, gonorrhea, typhoid

and in certain respiratory and urinary tract infections (Baltimore, 2005). Cefixime is available in

different formulations in different strengths for both pediatric and adult patients. Tablets and

capsules of cefixime are available in 200 mg and 400 mg while oral suspension of it comprises

of 100 mg/5ml and 200 mg/5ml. The recommended dose for patients above the age of 12 years is

50

200-400 mg/day and below age of 12 years recommended dose is 100-200 mg/day (Baltimore,

2005).

2.2.1 Physicochemical properties of cefixime:

Cefixime, a cephalosporin antibiotic, is white to almost white, slightly hygroscopic

powder; it has good solubility in methanol and is sparingly soluble in anhydrous ethanol,

whereas in water it is slightly soluble and practically it is insoluble in the ethyl acetate (British

Pharmacopoeia (BP, 2011). Cefixime was marketed in the form of Tablets and suspensions for

oral use (Ali and Mohiuddin, 2012).

2.2.2 Structural description of cefixime:

Cefixime had molecular weight 453.4 and had molecular formula C16H15N5O7S2.

Penicillins and cephalosporinswere structurally and functionally related with each other because

they shared a common β- lactam ring. Cephalosporins were composed of a six member ring

having sulphur atom attached to a β-lactam. Most of the cephalosporins were derived from 7-

aminocephalosporic acid (Naqvi et al., 2011).

Cefixime is a third-generation oral cephalosporin of the amino thiazole antibiotic group.

It differs from the other oral cephem antibiotics structurally in that it has vinyl group in 3-

position of aminothiazolyl ring and a β-2- aminothiazolyl-4-y1- (α-aIkoximine) acetamide side

chain at 7-position of cephem molecule. This modification in structure always supports efficient

oral absorption and has stability against Gram +ve and Gram -ve bacteria. Fig 2.1 and Fig 2.2

describes the structural representation of cefixime and its trihydrate.

C-CO-NH ”'”

CH=CH- CH

COOH

Fig 2.1: Chemical structure of cefixime.

51

Molecular formula of cefixime is C16H15N5O7S2; molecular mass is 453.5 and the melting

point is 218-225°C (Moffat et al., 2011).

Fig 2.2: Chemical structure of cefixime tri-hydrate.

As the tri-hydrate, the molecular weight is 507.50 and the Chemical Formula as cefixime

tri-hydrate is C16H15N5O7S2·3H2O (Baltimore, 2005).

2.2.2.1 Systematic (IUPAC) name:

In the International Union of Pure and Applied Chemistry (IUPAC), chemically its name

could be represented as (6R, 7R)-7-{[2-(2-amino-1, 3-thiazol-4-yl)-2-(carboxymethoxyimino)

acetyl] amino}-3-ethenyl-8-oxo-5-thia-1-azabicyclo[4.2.0] oct-2-ene-2 carboxylic acid (Reddy

and Reddy, 2012).

2.2.2.2 Structure activity relationship:

Chemically it was composed of a cephem nucleus that was attached to a six member ring

of dihydrothiazine. At position 3, cephem nucleus had a vinyl group for the absorption of intact

molecule through intestine and at 7-position acetic acid oxy- imine group and aminothiazole ring

were attached for antibacterial activity (Arshad et al., 2009).

52

2.2.3 Degradation and storage of cefixime:

Stability study of cefixime shows that cefixime is stable for 4 hours at short term room

temperature while stable for 16 hr at temperature of -20°C after preparation. Cefixime is stable

for 3 cycles of freeze and thaw, after storage at -20°C and then thawing at room temperature.

Stock solution of cefixime and internal standard is stable for 6 hr at room temperature and of 2

weeks at -20°C. In plasma, cefixime is stable for one month or more if stored at -20°C (Asiri et

al., 2005).

Regarding the degradation profile of cefixime, it was observed that 25% of cefixime was

degraded on heating at 80°C for 1 hr in 0.01 M NaOH. The drug was totally degraded if heated

for 4 hr at 80°C in 0.1 M NaOH. In acidic conditions, 25% of drug was degraded if heated with

0.01M HCl at 80°C for 2.5 hr. Degradation (100%) was observed at 80°C after 7 hr in 0.1M HCl.

The degradation was very rapid under oxidative conditions, as 25% drug was degraded if left at

25°C with 1% H2O2 in 3.5 hr (Gandhi and Rajput, 2009).

Tablets could be stored at room temperature for two years but suspension for 14 days

after reconstitution (Ali and Mohiuddin, 2012). The drug must be stored in a cool and dry place

and light should be avoided.

2.2.4 Pharmacological action of cefixime:

Cefixime is a cephalosporin antibiotic that acts as bacterial cell wall synthesis inhibitor,

cephalosporins are semi-synthetic antibacterial agents derived from a natural antibacterial

"cephalosporin-C", produced by a mould Cephalosporium acremonium.

Cephalosporins are classified to generations according to their antibacterial activity.

Succeeding generations generally have increasing activity against Gram -ve bacteria. Cefazolin,

cefradine, cefalexin and cefadroxil are commonly used first generation cephalosporins. Second

generation cephalosporins have similar activity to first generation against Gram +ve bacteria but

with greater activity against Gram -ve bacteria. Cefaclor and cefuroxime are classified as second

generation cephalosporins. The 3rd generation cephalosporins have more resistance to hydrolysis

by β-lactamases than other generations of cephalosporins and have a wider spectrum and greater

potency of activity against Gram-negative organisms.

53

Cefixime is effective against Enterobacteriaceae as well as against H. influenzae

(including strains having resistance to ampicillin), penicillin-susceptible Streptococcus

pneumonia, pathogenicNeisseria spp. (including gonococci having penicillin-resistance) and

certain Streptococcus species. Penicillin-resistant species include Staphylococcus spp.,

pneumococci, Enterococcus spp., Acinetobacter spp., Pseudomonas spp. and Listeria spp. Oral

cefixime is used to treat susceptible infectious diseases including pharyngitis, gonorrhoea, RTIs,

otitis media and infections of lower respiratory tract (Martindale, 2009).

For adults the dose of cefixime is 200 to 400 mg per day in single dose or two equally

divided doses. The dose recommended in children above 6 months is 8 mg/kg/day given as

single or two divided doses (BNF, 2011).

About 40-50% of cefixime in oral dose is absorbed from the GIT, either taken before

meal or after meals; however the rate of absorption of the drug may decrease due to food.

Absorption is fairly slow; peak plasma concentrations were reported between 2 to 6 hours

(Martindale, 2009).

Cefixime is effective in prophylaxis and treatment of biliary tract infections because

biliary excretion level of cefixime in bile is higher than other enterobacteriaceae family. The

level of cefixime is constant for 20 hours after giving single oral dose of 200 mg. This study was

conducted in patients with T-tube drainage for cefixime biliary excretion (Westphal et al., 1993).

The short-course cefixime therapy shows its effectiveness as other drug therapies (e.g.,

ofloxacin and amoxicillin) often used to treat infections of respiratory system, gonorrhea and

cystitis. In the treating community-acquired pneumonia, cefixime is effective as transitional

therapy, where by conversion of clinically stable patients from 3rd generation parenteral

cephalosporins to this agent results in the reduced direct and indirect both costs. So, in current

environment of health care in many countries, short course or transitional therapy with cefixime

is another advantage resulting in reduction of both indirect and direct costs (Quintiliani, 1996).

Infection of respiratory tract is one of the important and most common infectious disease

worldwide and in criticallyill patients in the developing countries RTI isthe leading cause of

morbidity and mortality (Navaneeth and Belwadi, 2002; Kumari et al., 2007).

Respiratoryinfections, in particular, those occurring in upper respiratory tract are seen with

54

greater frequency in adultsand have remarkable economic impact (Carroll and Reimer., 1996).

Cefixime is commonly used in upper respiratorytract infections (URTI). Some authors

recommendcefixime as first line antibiotic in community-acquiredURTI (Hedrick, 2010).

However, in some publications cefixime hasdemonstrated poor efficacy (Dreshaj et al., 2011).

Cefixime is frequently used to treat upper respiratory tract infections (URTI).

Therapeuticresponse of oral Tablet depends on its bioavailability. Cefixime has 40 to 50%

bioavailability due to its poor solubility (Nerurkar et al., 2013).

2.2.5 Antibacterial activity of cefixime:

Cefixime inhibits a wide range of Gram negative and Gram positive bacteria, especially

most of the members of family Enterobacteraceae, including the strains that produce the plasmid

mediated Beta-lactamases. The poor activity is reported against enterococci, Pseudomonas

aeruginosa, Staphylococcus aureus and anaerobes (Counts et al., 1988).

Cefixime shows broad spectrum actions against Gram +ve and Gram -ve aerobic bacteria

including Proteus vulgaris, Proteus mirabilis, Providencia stuartii, Haemophilus influenza,

Branhanella catarrhalis, Streptococcus pneumonias, Escherichia coli, Neisseria gonorrhoeae,

N. meringitidis, Klebsiella pneumoniaeandK. oxytoco (Brittain et al., 1985; Fuchs et al., l986;

Pfeffer et al., 1987). It is used to treat otitis media in children also (Risser et al., 1987) and adults

(Irvani et al., 1988; Kiani et al., 1988) and also is effective in treatment of typhoid fever (Bhutta

et al., 1994; Girgis et al., l995a,b; Malik et al., 1998; Rabbani et al., 1998; Cao et al., 1999).

Cefixime is also effective against Streptococcus pyogenes, S. pneumoiae and S. agalactiae. Most

strains of Streptococci belonging to the Lancefield group-F and G are only moderately sensitive

whereas Staphylococcus aureus, S. epidermidis, Enterococcus faecalis, Listeria monocytogenes,

Pseudomonas aeruginosa, P. cepacia, P. multophilia, Campylobacter jejuni and Bacteriodes spp

are generally resistant (Neu, 1988).

2.2.6 Route of administration and dosage of cefixime:

Cefixime is an oral antibiotic, readily absorbed from the gastrointestinal tract of both

adult and pediatricpatients; Cefixime can be administered to adults either as once daily dose of

400 mg or divided into twice-daily doses. A lower dosage of 200 mg daily has been used in

uncomplicated urinary tract infections. In pediatric patients, cefixime can be administered at a

55

dose of 4-8 mg/Kg as a single or twice daily dose. In patients of severe renal dysfunction

(creatinine clearance < 20m1/min), half of the standard dose of cefixime should be given once a

day (Francis et al., 1987). The recommended oral dosage in Japan is 100-200 mg/day in adult

and 3-6 mg/Kg for children, in twice daily doses, however in severe or non-responding

infections; the dose may be increased for adults up to 400 mg and for the children up-to l2

mg/Kg in twice daily doses.

2.2.7 Mode of action of cefixime:

Bactericidal activity of β-lactams (penicillin and cephalosporin) depends on the active

growth of those bacteria which will actively synthesize new cell walls. Cefixime inhibits the

synthesis of bacterial cell wall (that is essential for their growth and development).

Cefixime, a third generation cephalosporin and orally active drug is a cell wall synthesis

inhibitor (Memon et al., 1997). Cell wall protects the bacteria in unfavorable environmental

condition. Without cell wall bacteria were susceptible to environment and could die (Brahmaiah

et al., 2013). Cefixime performed its antibacterial activity by binding with penicillin-binding

proteins that were present in cell wall (Bhagawati et al., 2005).

2.2.8 Adverse effects of cefixime:

Adverse effects reported clinically in cefixime treated patients have usually been

transient and mild to moderate in case of severity. Diarrhea and some stool changes (soft stool

and loose stools, as distinguished front diarrhea), abdominal pain and nausea are the most

frequent adverse effects reported in adults and neonates or children administered once and twice

a day (Brogden and Campoli-Richards, 1989; Leggett et al., 1990). Cefixime suppressed the

Helicobacter pylori which mostly cause the recurrence of the gastric ulcer (Tatsuta et al., 1990).

Cefixime at highest concentration cause headache, rashes, dizziness and gastrointestinal

side effects (Azmi et al., 2013). It was reported that cephalosporin had convulsive activity to

some extent. It was caused by suppressing the inhibition of postsynaptic response that was

facilitated by gamma amino butyric acid receptor (Sugimoto et al., 2003).

Anaphylactic reactions (like shock and fatalities) have been observed by using cefixime.

Patient in whom some form of allergy, particularly to drugs, has demonstrated, antibiotics such

56

as cefixime should be given with caution. Treatment with cefixime or other broad spectrum

antibiotics may alter colon's normal flora and may cause overgrowth of the clostridia. Some

studies indicate that severe antibiotic associated diarrhea particularly Pseudomembranous colitis

is primarily caused by a toxin produced by Clostridium difficile (Baltimore, 2005).

2.2.8.1 Mutagenesis, carcinogenesis, impairment of fertility:

Lifetime studies have not been conducted to evaluate carcinogenic potential in animals.

Cefixime did not cause mutation in mammalian cells or bacteria, DNA or chromosomal damage

in the mouse micronucleus test. Cefixime did not affect fertility and reproductive performance in

rats, at doses up to 125-times the adult therapeutic dose (Baltimore, 2005).

2.2.9 Use of cefixime in mothers and children:

There are very few studies or data available on the use of cefixime in females and in

small age groups in human or trials in other animals.

2.2.9.1 Use in pregnant and nursing mothers:

2.2.9.1.1 Use in pregnancy:

For studies on pregnancy and reproduction, cefixime was administered in rats and mice at

400 times the greater dose than human dose and no harmful effects to fetus were revealed.

However no well-controlled and adequate studies have been performed in pregnant women.

During pregnancy cefixime should be given only if it is needed clearly, as studies on animals are

always not the prediction for human response (Baltimore, 2005).

In another study cefixime was used in pregnant woman for treatment of gonorrhea by

giving 400 mg single dose orally and cefixime was found a safe drug and can be used in

pregnancy for gonorrhea with better results (Miller, 1997).

2.2.9.1.2 Delivery and labor:

Cefixime is not studied for administration in delivery and labor. Treatment should only

be given if needed clearly (Baltimore, 2005).

2.2.9.1.3 Nursing mothers:

57

Excretion of cefixime in human milk is not clearly known. During treatment with

cefixime, nursing should be discontinued temporarily (Baltimore, 2005).

2.2.9.2 Use in pediatrics:

Cefixime has not been studied in children below 6 months of age for effectiveness and

safety of the drug. GIT adverse effects such as loose stools and diarrhea have been observed in

pediatric patients who have received the cefixime suspension, similarly as seen in the adults

receiving cefixime Tablets (Baltimore, 2005).

2.2.9.2.1 Role of cefixime in pediatric UTI:

Cefixime is highly effective against a broad range of Gram -ve and some Gram +ve

aerobic bacteria. In urine of children it attains a bactericidal concentration. Cefixime was only

found oral antibiotic used alone for serious forms of UTIs such as acute pyelonephritis. The drug

is used as a mono-therapy, 8 mg/kg dose as single or 12-hourly divided 2 doses for 14 days;

double dose on very 1st day of therapy. Alternatively, an intravenous antibiotic may be given for

first 3 days later on oral cefixime administration for remaining 11 days (switch-therapy). So, it is

concluded that cefixime is effective equally or more than other usual treatments for

uncomplicated UTIs, having low rate of adverse events. Various studies done across the world

indicated in their results that cefixime may be used in children as mono-therapy or as a switch-

therapy for treatment of uncomplicated UTI (Rao, 2005).

2.2.10 Use of cefixime as switch therapy:

Switching from parenteral to oral antimicrobials is successful technique in treating many

serious infections. Switch therapy results in significant cost saving also. Moreover it shortens the

stay in hospitals. Cefixime shows similar activity to ceftriaxone and cefotaxime sensitive

becteria with except of Staphylococcus aureus and penicillin-resistant Streptococcus

pneumoniae. It shows excellent tissue penetration and prolongs half- life resulting once-a-day

dosing of the drug. All these properties support the cefixime as switch therapy when a sensitive

pathogen is identified (Low, 1995).

58

2.2.11 Cefixime preparations in Pakistan:

It is important to compare different dosage forms, routes of drug administration and

preparations of various manufacturers. As therapeutic effects of antibiotics are mediated by their

access to the sites of action (target tissues) which is governed by rate and extent (completeness)

of absorption of a drug from its site of administration or bioavailability in biological system

(Gibaldi, 1984). Administration of different dosage forms of ampicillin using different routes in

sheep showed different bioavailability and pharmacokinetic parameters (Ahmad, 1984 and

Hafeez, 1985).

Cefixime is available in market of Pakistan in different dosage forms; routes and

preparations/formulations manufactured by different manufacturers and each manufacturing

company claim the superiority of their own product. These claims and increasing use of cefixime

in modern practice necessitates the assessment of bioavailability of these preparations.

There are a number (hundred plus) of brands of cefixime in market of Pakistan

manufactured by different manufacturers with different potencies, dosage forms, routes and

prices. Some of these brands (of famous companies) are listed below in the Table 2.2.

Table 2.2: Different brands of cefixime available in Pakistan.

Sr # Brand

Name

Manufacturer Dosage

Form

Potency Pack

Size

Route Retrail

Price

(Rs.)

1 Arocef Raazee Capsule

Suspension

400 mg

100 mg

200 mg

5's

30 ml

30 ml

Oral

-

-

249.00

119.00

150.00

2 Caricef Sami Capsule

Suspension

400 mg

100 mg

100 mg

200 mg

5's

30 ml

60 ml

30 ml

Oral

-

-

-

375.00

130.00

198.00

210.00

3 Cebosh Bosch Tablet 200 mg 10's Oral 230.00

59

Capsule

Suspension

400 mg

400 mg

100 mg

100 mg

200 mg

5's

5's

30 ml

60 ml

30 ml

-

-

-

-

-

235.00

235.00

120.00

190.00

190.00

4 Cef-OD CCL Tablet

Capsule

Suspension

200 mg

400 mg

100 mg

100 mg

200 mg

10's

5's

30 ml

60 ml

30 ml

Oral

-

-

-

-

210.00

245.00

115.00

199.00

199.00

5 Cefexol Nabiqasim Capsule

Suspension

400 mg

100 mg

200 mg

5's

30 ml

30 ml

Oral

-

-

225.00

125.00

199.00

6 Cefiget Getz Tablet

Capsule

Suspension

200 mg

400 mg

100 mg

200 mg

10's

5's

30 ml

30 ml

Oral

-

-

-

200.00

295.00

125.00

209.00

7 Cefim Hilton Capsule

Suspension

200 mg

200 mg

400 mg

100 mg

100 mg

200 mg

10's

5's

5's

30 ml

60 ml

30 ml

Oral

-

-

-

-

-

275.00

120.00

315.00

145.00

230.00

230.00

8 Cefix Standpharm Capsule

Suspension

200 mg

400 mg

100 mg

100 mg

200 mg

5's

5's

30 ml

60 ml

30 ml

Oral

-

-

-

-

123.50

250.00

123.53

183.60

183.60

9 Ceforal-3 Zafa Capsule

Suspension

400 mg

100 mg

5's

30 ml

Oral

-

160.00

95.00

10 Cefspan Barrett Capsule 400 mg 5's Oral 512.51

60

Hodgson Suspension 100 mg

200 mg

30 ml

30 ml

-

-

286.00

350.00

11 Ceftas Platinum Capsule

Suspension

200 mg

400 mg

100 mg

200 mg

5's

5's

30 ml

30 ml

Oral

-

-

120.00

240.00

130.00

195.00

12 Efix Highnoon Capsule

Suspension

400 mg

100 mg

5's

30 ml

Oral

-

250.00

120.00

13 Evofix Pharmevo Capsule

Suspension

400 mg

100 mg

100 mg

200 mg

5's

30 ml

60 ml

30 ml

Oral

-

-

-

470.00

115.00

170.00

170.00

14 Maxpan Indus Capsule

Suspension

200 mg

400 mg

100 mg

200 mg

10's

5's

30 ml

30 ml

Oral

-

-

-

186.30

186.30

105.80

197.80

15 Omixim Searle Capsule

Suspension

200 mg

400 mg

100 mg

200 mg

5's

5's

30 ml

30 ml

Oral

-

-

-

165.00

325.00

130.00

220.00

16 Tycef Helix Capsule

Suspension

400 mg

100 mg

100 mg

200 mg

5's

30 ml

60 ml

30 ml

Oral

-

-

-

225.00

115.00

190.00

185.00

17 Waybac Woodwards Capsule

Suspension

200 mg

200 mg

400 mg

100 mg

200 mg

10's

5's

5's

30 ml

30 ml

Oral

-

-

-

274.94

165.00

275.00

125.00

217.00

18 Xival Siza Capsule

Suspension

400 mg

100 mg

5's

30 ml

Oral

-

249.00

129.00

61

100 mg 60 ml - 169.00

19 Y-fix Adamjee Capsule

Suspension

400 mg

100 mg

100 mg

5's

30 ml

60 ml

Oral

-

-

141.17

70.58

111.76

20 Zylofixim Remington Suspension 100 mg

200 mg

30 ml

30 ml

Oral

-

120.00

190.00

2.3 Biopharmaceutical character of cefixime:

Biopharmaceutic is the branch of pharmaceutics in which influence of the formulation on

therapeutic effects of a drug product are studied. Biopharmaceutic deals with the study of

bioavailability, pharmacokinetics and co-relation within and in between In-vitro and In-vivo

parameters of drug (Parveen, 1982).

2.3.1 Disposition kinetics:

Drug disposition is the description of the simultaneous effects of the drug distribution and

its elimination. After intravenous injection, drug levels in plasma are initially high and rapidly

decline mono-phasically or in some cases poly-phasically. The validity and utility of

bioavailability measurements of any drug depends upon its pharmacokinetic behavior in body.

Pharmacokinetics is a discipline that deals with the study and mathematical characterization of

the time course of absorption (bioavailability), distribution, biotransformation and excretion of

drug products and its metabolites in the body, as well as relationship of these processes to

intensity and the time course of therapeutics and toxicology of the drugs (Parveen, 1982).

2.3.2 Pharmacokinetics models:

The course of mathematical characterization and evaluation of the relationship mentioned

above necessitate different styles or models to design the experiment and to process and interpret

the resultant data. Many different models presented in literature may conveniently be divided

into simple physiologic and pharmacological models out of which simple further may be

classified into two, linear and non-linear, broad categories of models. Linear models are widely

62

used for pharmacokinetics characterization and are good enough to explain the kinetic behavior

of most of the drugs (Parveen, 1982).

Pharmacokinetics is the mathematical description of the changes of concentration of

drugs within an organism. A common approach to study the pharmacokinetic behavior of drugs

is to depict the body as a system of compartments. In many instances these components which

are mathematical entities, have no physiological meaning, but are useful in describing the

disposition kinetics of a drug. A one compartment system is defined as one in which the drug

which enters the body is instantaneously distributed into the available spaces. The one

compartment model is useful for description of the time course of drugs in the plasma or urine,

after oral dose or intramuscular administration of the drugs. When distribution in-between the

central and the peripheral compartment are slow relative to elimination, it represents a two

compartment model. The two compartment open model accurately describes the

pharmacokinetics of most drugs after intravenous administration (Ahmad, 1983).

The extent of bioavailability and kinetic behavior plays a dominant role in selecting the

most promising antibiotics and determining the optimal treatment intervals (Ziv, 1975).

The concept of half life during the evaluation of disposition kinetics of drugs was first

introduced by Dost, (1949). It is widely used parameter and is a function of the system including

the constant of distribution, biotransformation and renal excretion of unchanged drug (Wagner

and Northham, 1967).

2.3.3 Bioavailability:

Human and animal life is constantly exposed to diverse type of chemicals deliberately or

accidently added to the environment and are found as pollutant. These chemicals range from

motor vehicles exhausts to industrial effluent, food additives, pesticides, insecticides and

pharmaceutical agents. The environmental pollutants may gain access to body directly or

indirectly through food chain. Human beings are exposed to a variety of chemicals for the

treatment of ailments. Domestic animals are intentionally given feed additives, veterinary drugs

and compounds for production improvement or protection by the insecticides or disinfectants.

All these compounds may pose a potential risk to animals if present in excessive concentrations.

The residues of all these chemical compounds may pass in the edible products from animals or

63

poultry and may cause a serious human health risk for consumers. Therefore the bioavailability

of such antibiotics to treat different infectious diseases is of basic importance for evaluation of

their beneficial or toxic effects (Butt, 1996).

Bioavailability is described as the rate and relative concentration of drug reaching the

general blood circulation. It may also be the extent of absorption of drug following its

administration by routes other than intravenous administration. Bioavailability is one of the the

certain factors that determine the relationship between the intensity of action and the drug

dosage. Different factors influencing the bio-availability include the first pass hepatic

biotransformation, solubility, chemical instability of the drug and nature of the drug formulation.

Moreover the factors that modify the absorption of a drug can change its bio-availability

(Baggot, 1977).Bioavailability (rate and extent of the absorption from a drug dosage form) is

reflected by the concentration-time curve of the administrated drug in systemic circulation.

Certain chemically equivalent drugs have produced clinically important and measurable

differences in the therapeutic effect which are the result of differences in bioavailability. Not

only bioequivalence has been found in products of different manufactures but there also have

been substantial variations in the bioavailability of different batches from the same company

(Parveen, 1982).Bioavailability parameters of 1st, 2nd, 3rd and 4th generation cephalosporins in

human being and in animals have been tabulated in Table 2.3.

64

Table 2.3: Reported values of some bioavailability parameters of cephalosporins in human beings.

Cephalosporin

Subjects

Dose

Route

Bioavailability Parameters

Reference

mg

mg

per

kg

maxC maxT AUC AUMC MRT

µg/ml hr µg.hr/ml /ml2µg.hr hr

Cephalexin Cats - 10

IV

- - - - 2.11

Albarellos et

al., 2011

Cefixime Children - - - 2.7 - - - - Alshare, 1999



Cefepime

Patients with

cystic

fibrosis - - - 141.3 - 1.73 - -

Ambrose et

al., 2002

Cefepime

Patients

(LRTIs)

- - - 71.2 - 3.92 - -

Ambrose et

al., 2002

Cefepime

Sepsis

- - - 94.2 - 3.42 - -

Ambrose et

al., 2002

Cefepime Young - - - 75.1 - 2.26 - -

Ambrose et

al., 2002

Cefepime Elders - - - 74.4 - 3.05 - - Ambrose et

65

al., 2002

Cefixime Healthy male

200

mg/10ml - Oral 3.38 4 26.5 - -

Asiri et al.,

2005

Cefixime -

200

mg/10ml - Oral 3.45 4 27.5 - -

Asiri et al.,

2005

Cefixime - 200 - Oral Tablet 2 - - - -

Baltimore,

2005

Cefixime - 400 - Oral Tablet 3.7 - - - -

Baltimore,

2005

Cefixime - 200 - Oral suspension 3 - - - -

Baltimore,

2005

Cefixime - 400 - Oral suspension 4.6 - - - -

Baltimore,

2005

Cefixime Young

400 mg OD

for 5 days - - 4.74 3.9 34.9 - -

Baltimore,

2005

Cefixime Elderly

400 mg OD

for 5 days - - 5.68 4.3 49.5 - -

Baltimore,

2005

Cefepime

Human

subjects 250 -

IV

16.3 - 34 - 2.3

Barbhaiya et

al., 1990c

Cefepime - 500 -

IV

31.6 - 62 - 2

Barbhaiya et

al., 1990c

Cefepime - 1000 - IV 66.9 - 137 - 2.2 Barbhaiya et

66

al., 1990c

Cefepime

(Young)

males 1000 -

IV

75.1 - 149 - 2.32

Barbhaiya et

al., 1992b

Cefepime

Young

females

- -

IV

90.1 - 172 - 2.24

Barbhaiya et

al., 1992b

Cefepime

(Elderly)

male

- -

IV

74.4 - 199 - 3.5

Barbhaiya et

al., 1992b

Cefepime

(Elder)

females

- -

IV

83.5 - 218 - 3.3

Barbhaiya et

al., 1992b

Cefprozil Fasting 250 - Oral 6.13 1.2 15 - 2.45

Barbhayia et

al., 1990

Cefaclor With food 250 - Oral 8.7 0.6 8.6 - 1.28

Barbhayia et

al., 1990

Cefprozil Fasting 250 - Oral 5.27 2 14.9 - 2.99

Barbhayia et

al., 1990

Cefaclor With food 250 - Oral 4.29 1.3 7.57 - 2.06

Barbhayia et

al., 1990

Cefprozil

Healthy male

volunteers 250 - Oral 6.1 1.5 16.1 - 2.6

Barbhayia et

al., 1990a

67

Cefaclor

Healthy male

volunteers 250 - Oral 10.6 0.5 8.7 - 1

Barbhayia et

al., 1990a

Cefprozil

Healthy male

volunteers 500 - Oral 11.2 1.4 32 - 2.7

Barbhayia et

al., 1990a

Cefaclor

Healthy male

volunteers 500 - Oral 17.3 0.7 17.5 - 1.2

Barbhayia et

al., 1990a

Cefprozil Humen 250 - Oral 6.1 1.5 16.4 - 2.7

Barbhayia et

al., 1990b

Cefprozil - 500 - Oral 10.5 1.5 31.1 - 2.7

Barbhayia et

al., 1990b

Cefprozil - 1000 - Oral 18.3 2 61.2 - 3.1

Barbhayia et

al., 1990b

Cefprozil

Beagle dogs 125 -

IV

77.6 - 7043 - 110

Barbhayia et

al., 1992a

Cefprozil

Beagle dogs 125 -

Oral

26.6 - 5572 - 183

Barbhayia et

al., 1992a

Cefixime Dogs

- 6.25

IV

- - 5.2 0.312 -

Bialer et al.,

1987

Cefixime Dogs

- 25

IV

- - - - -

Bialer et al.,

1987

Cefpodoxime Healthy adult 100-400 -

Oral

1-4.5

1.9-

3.1 - - - Borin, 1991

68

Cefoperazone Neonates 50 - 136 - - - -

Bosso et al.,

1983

Ceftriaxone

Healthy

volunteers 2000 -

IV

239 0.5 1459 - -

Bourget et

al., 1993

Ceftriaxone

Pregnant

women 2000 - Infusion 224.3 1 1588 - -

Bourget et

al., 1993

Cefixime

Normal

subjects 50 - - 1 - 7 - -

Brittain et al.,

1985

Cefixime - 100 - - 1.5 - 11 - -

Brittain et al.,

1985

Cefixime - 200 - - 2.6 3.4 23 - -

Brittain et al.,

1985

Cefixime - 400 - - 3.9 4.3 36 - -

Brittain et al.,

1985

Cefixime

Healthy

subjects 200 - -

2.0-

2.6

3.0-

4.0 - - -

Brogden and

Campoli-

Richards,

1989

Cefepime Neonates - 50 - 0.89 - - - -

Capparelli et

al., 2005

Cefoperazone Calves - - - - - - - 1.43

Carli et al.,

1986

69

Cefoperazone

In women 2-

3 days after

postpartum 1000 -

IV

- - 177.61 - -

Charles and

Bryan, 1986

Cefotaxime

1000 -

IV

- - 30.22 - -

Charles and

Bryan, 1986

Cefpodoxime Healthy adult 400 - Oral 3.8 - - - -

Chugh and

Agrawal,

2003

Ceftolozane

Neutropenic

mice - 25 - 25.2 0.25 13.3 - -

Craig and

Andes, 2013

Ceftolozane - - 100 - 110 0.25 55.5 - -

Craig and

Andes, 2013

Ceftolozane - - 400 - 574 0.25 299 - -

Craig and

Andes, 2013

Cefoperazone

Healthy male

and female

adult 2000 -

IV

288.9 - 1215.9 - -

Deeter et al.,

1990

Cefotaxime

- 2000 -

IV

132.7 - 182 - -

Deeter et al.,

1990

Ceftriaxone

- 2000 -

IV

261.6 - 3144.4 - -

Deeter et al.,

1990

Ceftazidine - 2000 - IV 167.3 - 409.2 - - Deeter et al.,

70

1990

Ceftizoxime

- 2000 -

IV

205.2 - 516.4 - -

Deeter et al.,

1990

Cefixime

Normal

subjects 200 - Oral 2.5 2.83 - - -

Dhib et al.,

1991

Cefixime

Uremic

patients 200 - Oral 2.83 - - - -

Dhib et al.,

1991

Ceftazidime Healthy adult 2000 - - 69-90 - - - -

Drusano et

al., 1984

Cefixime - 200 - Oral Tablet 2.5 3.7 18 - -

Duverene et

al., 1992

Cefixime - 200 - IV injection - - 58 - -

Duverene et

al., 1992

Cefixime Sheep - - - 0.63 - 6.88 - -

Eldalo et al.,

2004

Cefixime Cattle - - - 0.5 - 8.98 - -

Eldalo et al.,

2004

Cefazolin

In parturients

undergoing

cesarean

surgery 2000 - - - - 436 - -

Elkomy et

al., 2014

Cefixime Healthy 200 - IV solution - - 47 - - Faulkner et

71

volunteers al., 1988

Cefixime

Healthy

volunteers 200 - Oral solution 3.2 - 26 - -

Faulkner et

al., 1988

Cefixime

Healthy

volunteers 200 - Oral capsule 2.9 - 24 - -

Faulkner et

al., 1988

Cefixime

Healthy

volunteers 400 - Oral capsule 4.8 - 39 - -

Faulkner et

al., 1988

Cefixime Healthy male 400 - Oral suspension 4.67 - - - -

Faulkner et

al., 1989

Cefixime - 400 -

Oral suspension

4.1 - - - -

Faulkner et

al., 1989

Cefixime

Healthy male

subjects 400 -

Oral suspension

4.67 - - - -

Faulkner et

al., 1989

Cefixime - 400 -

Oral suspension

4.1 - - - -

Faulkner et

al., 1989

Cefixime - 400 - Oral solution 4.27 - - - -

Faulkner et

al., 1989

Ceftriaxone

Calves

(buffalo) - 10

IV

- - 40 - -

Gohil et al.,

2009

Ceftriaxone

Calves

(buffalo) - 10 IM 16 - 30 - -

Gohil et al.,

2009

Ceftazidime Female - 10 IV - - 209.74 - 3.96 Goudah and

72

dromedary

camels

Sherifa, 2013

Ceftazidime - -

10

IM - - 195.23 - 4.84

Goudah and

Sherifa, 2013

Cefepime

Healthy

rabbits - - IM 114.9 0.5 300.2 1099.1 3.65

Goudah et

al., 2006

Cefepime

Febrile

rabbits - - IM 130.4 0.6 646.9 2915.5 4.56

Goudah et

al., 2006

Cefotaxime Neonates - 25 - 171 - - -

Gouyon et

al., 1990

Cefixime

Healthy

subjects 400 - Oral 4.9 4.9 40 - -

Guay et al.,

1986

Cefoperazone

Cross bred

calves - 4

IV

- - 29 46.3 1.6

Gupta et al.,

2007

Cefoperazone

Cross bred

calves - 20 IM 9.76 0.75 15.7 56.6 3.62

Gupta et al.,

2008

Cefixime

Healthy

subjects 400 - Oral 4.9 4.9 40 - -

Guay et al.,

1986

Cefixime

Healthy adult

male 400 - Oral 4.9 4 38 - -

Healy et al.,

1989

Cefuroxime

Malnourished

rats - 2.2

Oral

- - - - 73.2

Hernandez et

al., 2008

73

Cefuroxime

Controlled

rats

- 2.2

Oral

- - - - 63

Hernandez et

al., 2008

Cefixime

Healthy

volunteers 400 - - 2.2 - 26 - 7.47

Jieying et al.,

1996

Cefepime

Febrile

buffalo

calves - 10

IV

- - 101 - -

Joshi and

Suresh, 2009

Cephalexin Healthy adult 1000 - Oral 23.4 - - - -

Kalman and

Steven, 1990

Cefadroxil Healthy adult - - Oral 13.7 - - - -

Kalman and

Steven, 1990

Cephradine Healthy adult 1000 - Oral 21.3 - - - -

Kalman and

Steven, 1990

Cephalothin Healthy adult 1000 - Parenteral-IV 30 0.25 - - -

Kalman and

Steven, 1990

Cephapirin Healthy adult 1000 - Parenteral-IV 67 0.25 - - -

Kalman and

Steven, 1990

Cefazolin Healthy adult 1000 - Parenteral 188 0.25 - - -

Kalman and

Steven, 1990

Cefuroxime Healthy adult 1000 - Oral 6.3 - - - -

Kalman and

Steven, 1990

74

Cefuroxime Healthy adult 1000 - Parenteral 38-64 - - - -

Kalman and

Steven, 1990

Cefamandole Healthy adult 1000 - Parenteral 139 - - - -

Kalman and

Steven, 1990

Cefoxitin Healthy adult 1000 - Parenteral 125 - - - -

Kalman and

Steven, 1990

Cefmetazole Healthy adult 1000 - Parenteral 130 - - - -

Kalman and

Steven, 1990

Cefotetan Healthy adult 1000 - Parenteral

79-

132 - - - -

Kalman and

Steven, 1990

Cefaclor Healthy adult - - Oral 13.1 - - - -

Kalman and

Steven, 1990

Cefdinir Healthy adult 300 - Oral 2

2.0-

4.0 - - -

Kalman and

Steven, 1990

Cefoperazone Healthy adult 1000 -

IV

153 - - - -

Kalman and

Steven, 1990

Cefotaxime Healthy adult 1000 -

IV

102 - - - -

Kalman and

Steven, 1990

Ceftizoxime Healthy adult 1000 -

IV

85 - - - -

Kalman and

Steven, 1990

Ceftriaxone Healthy adult 1000 -

IV

150 - - - -

Kalman and

Steven, 1990

75

Ceftazidime Healthy adult - - Parenteral 69 - - - -

Kalman and

Steven, 1990

Cefixime Healthy adult 400 - Oral 4.8 - - - -

Kalman and

Steven, 1990

Cefroxadine Healthy adult - - - 17.62 1.44 - - -

Kang et al.,

2006

Cefadroxil Healthy adult 500 - - 16.04

1.5-

2.0 - - -

Kano et al.,

2008

Cefuroxime

Healthy

volunteers 500 - Oral 5.24 1.68 15.6 - 2.78

Kaza et al.,

2012

Cefuroxime

Healthy

volunteers 500 - Oral 4.86 1.78 15.1 - 2.89

Kaza et al.,

2012

Cefixime

Healthy male

and female

volunteers 200 - Oral Tablet 2.95 3.46 20.89 - -

Kees et al.,

1990

Cefixime - 200 - Oral syrup 2.43 3.42 17.83 - -

Kees et al.,

1990

Cefixime - 200 - Oral suspension 3.41 3.33 25.84 - -

Kees et al.,

1990

Cefixime

Healthy

volunteers 200 - Oral Tablet 3

3.3-

3.5 20.9 - -

Kees et al.,

1990 and

Kees and

76

Naber, 1990

Cefixime - 200 - Oral syrup 2.4

3.3-

3.5 17.8 - -

Kees et al.,

1990 and

Kees and

Naber, 1990

Cefixime - 200 -

Oral dry

suspension 3.4

3.3-

3.5 25.8 - -

Kees et al.,

1990 and

Kees and

Naber, 1990

Cefixime Healthy male 200 - Oral Tablet 3.38 4.7 - - -

Lan-Ying et

al., 2004

Cefixime - 200 - Oral capsule 3.29 4.6 - - -

Lan-Ying et

al., 2004

Cefixime - 200 -

(Domestic)

capsule 2.97 3.39 25.9 - -

Lei et al.,

2003

Cefixime - 200 -

(Imported)

capsule 2.83 3.33 24.7 - -

Lei et al.,

2003

Cefixime

Renal

patients

200 mg BD

for 2 days - - 3.4 - - - -

Leroy et al.,

1995

Cefaclor

Female

subjects 500 - Oral with water 13.4 1.25 21.2 - -

Li et al.,

2009

Cefaclor Female 500 - Oral with juice 11.7 1.5 20.5 - - Li et al.,

77

subjects 2009

Cefpodoxime - 400 -

Oral

3.9 3.1 22.4 130.3 5.7

Liu et al.,

2005

Cefixime - 400 -

Oral

3.4 4.8 25.6 164.2 6.5

Liu et al.,

2005

Cefixime Chinese men 400 - - 6 5.2 - - -

Liu et al.,

2007

Cefixime - - - - - 2 - - - Low, 1995

Cefixime

Renal

patients 100 - - 2 6 - - -

Maeda et al.,

1986

Ceftriaxone Calves (cow) - 10

IV

- - 57 - -

Maradiya et

al., 2010

Ceftriaxone Calves (cow) - 10 IM 15 - 28 - -

Maradiya et

al., 2010

Ceftriaxone

Cardiac

patients 1000 -

IV

- - 853 - 15

Martin et al.,

1996

Cefepime Mice - 80 - 90 - 75.7 - 0.58

Mathe et al.,

2006

Ceftriaxone Healthy adult 1000 - IM 79 1.5 - - -

Meyers et al.,

1983

Ceftolozane

Females /

males 500 - - 42.6 1 98.6 - -

Miller et al.,

2012

78

Cefixime

Healthy


Ming-Hui,

2009

Cefixime - 200 - Oral capsule 2.81 3.31 21.2 - -

Ming-Hui,

2009

Cefixime - 200 - Oral 2.56 3.17 19.9 - -

Min-Ji et al.,

2004

Cefixime - 200 - Oral 2.32 3.5 19.1 - -

Min-Ji et al.,

2004

Cephalexin

Healthy male

and female

volunteers 500 - - 23.84 0.98 39.14 - 1.89

Mircioiu et

al., 2007

Cephalexin

Healthy

volunteers 500 - - 19.05 1.05 32.46 65.12 1.93

Mohamed et

al., 2011

Cephalexin

Healthy

volunteers 500 - - 17.36 1.1 33.35 72.46 2.04

Mohamed et

al., 2011

Cephalexin

Healthy

volunteers 500 - - 17.31 1.1 31.32 65.64 1.98

Mohamed et

al., 2011

Ceftazidime Dogs -

20 IV

- - 119 - 1.31

Monfrinotti

et al., 2009

Ceftazidime - -

25

IM - - 202 - 2.2

Monfrinotti

et al., 2009

Ceftazidime - - 25 SC - - 156 - 2.95 Monfrinotti

79

et al., 2009

Cefixime

Healthy male

volunteers 200 - Oral 3.3 4 - - -

Montay et al.,

1989

Cefixime

Healthy male

volunteers 400 - Oral 4.4 4 34 - -

Montay et al.,

1991

Cefixime Children - 1.5 - 0.6 4 4.1 - -

Motohiro et

al., 1986

Cefixime Children - 3 - 1.2 4 8.3 - -

Motohiro et

al., 1986

Cefixime - 50 - Oral granules 1.26 4 9.63 - -

Motohiro et

al., 1986

Cefixime - 50 - Oral capsule 1.16 4 7.82 - -

Motohiro et

al., 1986

Ceftriaxone Neonates - 50 - 153 - - - -

Mulhall et

al., 1985

Cefixime

Healthy

volunteers 50 mg bid - - 0.7 - - - -

Nakashima et

al., 1987

Cefixime

Healthy


Nakashima et

al., 1987

Cefixime

Healthy


Nakashima et

al., 1987

Cefixime - 200 - - 2.5 3 - - - Nies, 1989

80

Ceftriaxone Humen

water

asdiluent - IM 44.6 2.5 578 - -

Patel et al.,

1982

Ceftriaxone -

lidocain

asdiluent - IM 41.9 3 577 - -

Patel et al.,

1982

Cefepime Calves - 5

IV

- - 47.73 190.3 3.95

Patel et al.,

2006

Cefepime Cow (calves) - 5

IV

- - 48 - -

Patel et al.,

2006

Cefepime Cow (calves) - 5 IM 8.6 - 47 - -

Patel et al.,

2006b

Cefepime Sheep - 20

IV

- - 136 - -

Patel et al.,

2010

Cefepime Sheep - 20 IM 26 - 141 - -

Patel et al.,

2010

Cefepime Goat - 10

IV

- - 78 - -

Patni et al.,

2008

Cefepime Goat - 10 IM 16 - 93 - -

Patni et al.,

2008

Cefpodoxime

Male and

female

subjects 200 - Oral 3.03 3.67 33.3 - -

Peter et al.,

1992

Ceftriaxone Males and 2000 - IV 306 0.5 155.7 - 9.1 Pletz et al.,

81

females 2004

Cefpirome

Buffalo

calves - 10 IM 9.04 0.5 28.7 107.7 3.76

Rajput et al.,

2007

Cefpirome

Crossbred

calves - 10 IM 10.1 0.75 31.7 105.1 3.31

Rajput et al.,

2012

Cefoxitin Neonates - 30 - 69.8 - - - -

Regazzi et

al., 1983

Cefuroxime Neonates - 10 - 24.2 - - - -

Renlund and

Pettay, 1977

Cefixime - 400 - Oral 4 - - - -

Robert et al.,

2001

(Bioxime)

Cefuroxime

Healthy

volunteers 500 - Oral 5.562 1.78 17.308 - -

Sabati et al.,

2014

(Zinnat)

Cefuroxime

Healthy

volunteers 500 - Oral 6.044 1.76 18.13 - -

Sabati et al.,

2014

Cefotaxime Bufalo calves - 13 - - - 18.3 21.6 -

Sharma and

Anil, 2003

Cefotaxime Bufalo calves - 10

SC

- - 14.3 40.5 2.83

Sharma and

Anil., 2006

Ceftazidime

Febrile

buffalo

calves - 10

IV

- - 217.3 952.9 -

Sharma and

Shah, 2012

82

Cefotaxime

Buffalo

calves

febrile)) - 10

IV

- - 15.8 - -

Sharma et al.,

2006

Cephradine

Healthy adult

male 250 - PO 11.49 0.76 - 14.23 17.81

Shoaib et al.,

2008

Cefixime

Healthy

volunteers 200 - Oral Tablet 3 3.5 22 - -

Shu-Ying et

al., 2009

Cefixime - 200 - Oral capsule 2.8 4.4 22.6 - -

Shu-Ying et

al., 2009

(Cis-isomer)

Cefprozil

Lactating

females - - - 14.8 2 54.8 - 3.38

Shyu et al.,

1992

(Trans-

isomer)

Cefprozil - - - - 1.9 2 6.2 - 3.41

Shyu et al.,

1992

Ceftriaxone Calves - 10

IV

- - - - 94

Soback and

Ziv, 1988

Ceftriaxone Calves - 10 IM - - - - 137.6

Soback and

Ziv, 1988

Ceftazidime Male 1000 -

IV

- - 153.2 - -

Sommers et

al., 1983

Ceftazidime Female 1000 -

IV

- - 179.8 - -

Sommers et

al., 1983

83

Ceftazidime Male 1000 - IM - - 120.5 - -

Sommers et

al., 1983

Ceftazidime Female 1000 - IM - - 169.4 - -

Sommers et

al., 1983

Cefoperazone Healthy adult 1000 -

IV

61.9 1.9 - - -

Sootornpas et

al., 2011

Ceftazidime Juvenile

loggerhead

sea turtles -

20

IV

- - 1567 49860 31.7

Stamper et

al., 1999

Ceftazidime

- -

20

IM - - 1393 44169 31.7

Stamper et

al., 1999

Cefixime

Healthy male

volunteers 400 - - 3.7 6.7 - - -

Stone et al.,

1988

Ceftriaxone

Sheep - 10

IV

- - 43 - -

Swati et al.,

2010

Ceftriaxone

Sheep - 10 IM 16 - 48 - -

Swati et al.,

2010

Ceftifur Healthy pigs - -

IV

12.9 0.5 168 4535 27

Tantituvanont

et al., 2009

Ceftriaxone

Goat - 20

IV

- - 78 - -

Tiwari et al.,

2009

Ceftriaxone Goat - 20 IM 22 - 67 - - Tiwari et al.,

84

2009

Ceftriaxone

Transplant

recepients 2000 -

IV

318 - - - 29.9

Toth et al.,

1991

Ceftriaxone

Normal

subjects 2000 -

IV

257 - - - -

Toth et al.,

1991

Ceftizoxime

Female and

male subjects 2000 -

IV

114.37 - 192.52 - -

Valle and

Marc, 1991

Ceftizoxime - 2000 -

IV

125.86 - 141.93 - -

Valle and

Marc, 1991

Cefixime

Patients of T-

tube drainage - - - 2.3 5.1 20 - -

Westphal et

al., 1992

Cefixime

Healthy


Yan et al.,

2003

Cefixime

Healthy

volunteers 200 - Granules 3.1 3.2 28.5 - -

Yan et al.,

2003

Cefixime

Fasting

subject 200 - - 2.7 3.7 25.4 - -

Yaoguo et

al., 1994

Cefixime

Non-Fasting

subjects 200 - - 1.7 3.3 13.9 - -

Yaoguo et

al., 1994

Cefixime

Patients with

RTIs (M&F) 200 - - 2.64 4 21.24 - -

Yi et al.,

1995

Cefixime Healthy male 200 - Oral capsule 2.33 4.5 15.9 - - Yu-fei et al.,

85

2004

Cefixime - 200 - Oral capsule 2.28 4.28 16 - -

Yu-fei et al.,

2004

Cefixime Healthy male 400 - Oral Tablet 4.75 - 45 - -

Zakeri et al.,

2008

Cefixime - - - Oral Tablet 4.73 - 45.2 - -

Zakeri et al.,

2008

Cefuroxime

sodium

Beagle

dogs - 40

IV

84.2 0.54 121.5 187.2 1.54

Zhao et al.,

2012

Cefuroxime

lysine - - -

IV

92.46 0.5 130.9 181.1 1.39

Zhao et al.,

2012

Cefuroxime

lysine Rats - 67.5

IV

- - 45.29 16.84 0.37

Zhao et al.,

2012b

Cefuroxime

lysine Rats - 67.5 IP - - 58.12 55.33 0.93

Zhao et al.,

2012b

Cefuroxime

lysine Rats - 67.5 IM - - 55.31 36.17 0.65

Zhao et al.,

2012b

Ceftriaxone

Males and

females 1000 - IM 130.6 1.4 1493 - -

Zhou et al.,

1985

Ceftriaxone - 1000 -

IV

- - 1507 - -

Zhou et al.,

1985

86

RTI = Lower Respiratory Tract Infections PO = Per Oral OD = Once Daily

IV = Intra Venous IM = Intra Muscular SC = Sub Cutaneous

130

2.3.4 Urinary excretion and renal clearance:

The concept of renal clearance has proved useful in estimating kidney function. The

clearance rate of any substance is the volume of plasma which contains the amount of

substance excreted through urine in a unit time. The term clearance can be applied for any

substance in the plasma which appears in the urine by whatever process it reaches the urine,

filtration, secretion or excretion or a combination of these. Clearance rates of suitable

substance reveal the glomerular filtration rate. Creatinine is completely filtered at the

glomerulus and is not reabsorbed in the tubules and the endogenous creatinine renal clearance

is very widely used in clinical practice to give an estimate of GFR (Ahmad, 1983).

2.3.5 Bioequivalence:

Bioequivalence may be defined as a bioavailability study comparing two or more

different dosage form or different formulations of a dosage form of the same parent drug,

when comparing different dosage forms intravenous injection or oral solution is taken as

acceptable standard. Bioequivalence tells us that a drugs in given two or more similar dosage

forms reach the general/blood circulation at same relative rate and to same relative extent, in

which the profiles of plasma level of the drug are achieved using the two dosage forms are

super imposable (Remington, 1975). Drug product of a chemical equivalents whether

different dosage forms or different formulation of a dosage form are assumed bioequivalent if

the difference between the bioavailability of these products is not significant i.e. not more

than ±20%. Some pharmaceutical equivalents may be equivalent in regarding their absorption

rate and considered bioequivalent. Such differences in absorption rate are intentional and also

reflected in its labels. This is due to the fact, that when in chronic diseases, the attainment of

effective body drug concentration is not essential or when it is considered medically

insignificant for the particular product (Parveen, 1982).

The efficacy of a single dose of a drug is a function of both the rate and extent of

absorption of drug, so, to assure the bioequivalence of two dosage forms of same

formulation, not only the drug amount absorbed from each is important, the absorption rate of

drug from each drug product must also be comparable (Gibaldo, 1977), e.g., the drug may be

100% absorbed following oral administration and yet be ineffective due to a release rate that

is slow that the concentration in the blood at no time achieves the required level. Conversely,

the release may be too fast, giving the patient such a rapid result that undesirable side effects

are experienced.

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Generally, bioequivalence should be shown for the drugs which are used in serious

illness, drugs which have steep dose response curves or serious undesirable effects and finally

those drugs which have poor water solubility or convert to water insoluble forms in the

gastrointestinal tract, making dosage form factor as possible rate limiting step in the

absorption process. Several recent studies have demonstrated bioequivalence of chemically

equivalent drug products (Barr et al., 1972; Chiou, 1972; Wagner et al., 1973).

Bioequivalence requirements are imposed by FDA for In-vivo and In-vitro testing of the

specified drug products.

2.3.6 Studying pharmacokinetics of a drug:

Prior to bioavailability or bioequivalence study, important task for the investigator is

to make decision about the nature and type of experimental design, dose system, sampling

compartment, extent of estimation and method of estimation. He has to select one way out of

different followings according to the need and facilities available:

Experimental design: - Complete crossover, Latin Square, Balanced incomplete block design.

Dose system: - Single dose, multiple dose.

Sampling compartment: - Blood level data, urinary excretion data.

Extent of estimation: - Parent drug, total drug (active and bio-transformed form of drug).

In comparing of bioavailability of two or more drug products, a complete crossover or

any other statistically sound experimental design is necessary to have a direct comparison of

the absorption of each drug product in the same individual and to estimate the biological

effect. A sufficient time interval between the administrations of two drug products is given to

an individual for avoiding carryover effects of the drugs (Parveen, 1982).

2.4 Factors effecting drug pharmacokinetics:

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Most antibacterial drugs have a wide therapeutic margin; therefore individualized dosage

is not essential. However, the dose must be determined relative to age, absorptive surface

area, body composition and maturation of body systems.

Antibiotics have a great role in treatment of many human and animal's infections. For

treatment of microbial infections, an effective concentration of antibacterial agent should

reach at site of infection and it should be maintained there for an appropriate time. This

achieved concentration is dependent on systemic availability of drugs. This bioavailability of

drug depends upon itsdosage form, route of administration, dosing rate and frequency, ability

to reach at the site of infection. Physicochemical characteristics of the drug also affect the

pharmacokinetic characteristics like drug concentration, rate and extent of absorption,

distribution pattern and mechanism of drug elimination. Susceptibility of microorganisms to

the antibiotics is also an important clinical aspect for drug's efficacy. Thus an effective

antibiotic therapy depends on the bacterial susceptibility, dosing rate and pharmacokinetic

characteristics of the drugs.

Correlation within In-vitro and In-vivo Parameters:

In the field of biopharmaceutic, the study of the physical and pharmaceutical factors

influencing the bioavailability of a drug from its different preparations has been very

interesting topics for many research workers (Aguiar et al., 1968).

2.4.1 Particle size, viscosity and surface area:

From intramuscular dosage forms of the drug, absorption may be affected by the

viscosity of suspension. The effect of the viscosity on the drug absorption was evaluated by

administration of suspensions, having same particle size and same formulation. In different

cases the effect of viscosity on the drug absorption could be negligible, as in the case of

chloramphenicol (Kitamori et al., 1976). By all possible manipulation in physical properties

of chloramphenicol to yield better drug absorption, the reduction of particle size is the most

widely exploited. Increased absorption due to reduction of particle size (Renihold, 1945) is

the result of increased dissolution, which is in turn the result of a large surface area being

exposed to the fluids in the gastrointestinal tract or to other sites of administration. The

breakdown of a 3 mm3 into 1 mm3 particles results into a 300% increased in the exposed

surface area.

2.4.2 Role of drug solubility:

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Cefixime is recommended as first line antibiotic in community-acquired URTI

(Hedrick, 2010) however; in some publications cefixime has been demonstrated as drug

withpoor efficacy (Dreshaj et al., 2011). Therapeutic efficacy of an oral product depends on

its absorption in GIT. However for absorption, the drug is needed to be solubilized. Solubility

has a crucial role for bioavailability of oral drug, particularly for the drugs having low

gastrointestinal solubility and having low permeability . Bioavailability can be enhanced by

improvement of solubility of a drug (Suchetha et al., 2010). Cefixime is not soluble in acidic

medium. After its oraladministration; it is slowly and incompletely absorbedfrom the

gastrointestinal tract, which results into poorbioavailability (Ali and Omair, 2012). A drug's

therapeutic actions depend upon delivery of the medicaments from its dosage form to the site

of action at a rate and amount sufficient to produce thedesired pharmacological response.

Oral ingestion is commonly employed as the most convenient route of drugdelivery due to

different reasons such as its ease of administration, cost-effectiveness, least sterility

constraints, high patientcompliance and flexibility in the design of dosage form. Poor

bioavailability is the major challenge with oral dosage forms. Different factors which may

affect oral bioavailabilityinclude; aqueous solubility, dissolution rate, drug permeability, first-

pass metabolismand pre-systemic metabolism. Low permeability and poor solubility are the

most frequent causesof low oral bioavailability (Bajaj et al., 2011). Cefixime has low

solubility and reasonable permeability. This study was conducted to evaluate

whetherimprovement in solubility of cefixime oral Tabletenhances its efficacy in upper

respiratory tract infection. In this study, both the study drugs (improved form and

conventional one) significantly reducesymptoms of URTI on day 5 from baseline. Reductions

inclinical symptoms were significantly more in patientstreated with improved formulation of

cefixime thanconventional cefixime Tablet. This result suggested thatimproved formulation

of cefixime shows fasterimprovement in signs and symptoms of URTI thanconventional

cefixime Tablet. Greater efficacy ofimproved formulation of cefixime may be due to

higherbioavailability of cefixime (Nerurkar et al., 2013).

2.4.3 Influence of genetic variation on drug's pharmacokinetics:

Many developing countries, such as Pakistan, import raw and finished drugs.

Preclinical and clinical trials for drug development in drug exporter countries are done. In

certain cases the environmental conditions and genetic makeup of animals in importing

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countries are different than in exporting countries. In several studies the optimal dosage,

pharmacokinetic behavior, urinary excretion and renal clearance of the imported drugs under

investigation were different under the indigenous condition than the values mentioned on the

product inserts or in the manufacture's literature. The term "geonetics" describes the influence

of environment on the genetics and it is manifested by physiological and biochemical

characteristics / parameters which ultimately have an effect on bio-disposition and fate of

drugs in the body of a population (Nawaz, 1982; Nawaz and Shah, 1985; Nawaz, 1994;

Muhammad, 1997). These geonetical influences has been reported for pH of blood and urine,

plasma proteins, metabolism of drugs and renal functions in cows, buffaloes, goats and sheep

(Nawaz et al., 1988). It may be concluded from such studies that geonetical conditions may

influence the physiological and biochemical parameters and thus ultimately fate and

disposition kinetics are affected resulting in changed response towards the drug. Several

studies in animals show that bio-disposition of certain drugs, i.e. sulfonamides; under

indigenous condition is different from pharmacokinetics recorded elsewhere (Nawaz et al.,

1989).

So the optimal drug dosage regimen is based on pharmacokinetic profile in species

and also the environment where which drug is being employed clinically.

2.4.4 Dehydration:

The dehydration occurs in body due to any of the following reasons:-

Environmental water deprivation.

Excessive sweating in warm climatic and during exercise.

In some diseases like polyuria and diarrhea, etc.

A number of physiologic and biochemical changes have been attributed to temporary

dehydration which can significantly modify the disposition of drugs in the body. When

electrolyte and water changes in tropical marine sheep, exposed to dehydration in summer

was observed (Macfarlane, 1961), it was found that after an initial increase, the plasma and

extracellular volume decreased as much as 45% while concentrations of hemoglobin and

plasma proteins increased by 60%. In plasma K and Na concentrations were increased less

than that of Hb.

In last 10 years, the electrolyte and urea concentrations during dehydration, the renal

regulation of acid-base equilibrium, effect of mild dehydration in creatinine clearance rate,

135

effects of acute water restrictions on plasma proteins, effect of dehydration on systemic fluid

balance and subjective sensations where determined in different animals by many worker

(Rolls et al., 1980). It is evident from the findings of reported dehydration studies that during

such condition the kinetic of a drug may significantly be changed resulting in altered efficacy

and toxicity, which might necessitate a new basis of drug selection and dosage regimen

modification.

2.4.5 Influence of age on cefixime pharmacokinetics:

Mean maximum plasma drug concentration and the area under the time and the

plasma drug value curve were increased by 26% and 20%, respectively, in elder subjects as

compare to young subjects after oral administration of 400 mg per day of cefixime for 5 days

(Silber et al., 1988). However, dose adjustment according to age alone should not be

necessary (Brogden and Campoli-Richards, 1989).

2.4.5.1 Influence of age on drug absorption:

Drug absorption is characterized by passage of the drug from its site of administration

into the blood circulation stream. Therefore, developmental changes during the first few days,

months, or years of life influence both the rate and extent of oral drug absorption in pediatric

patients. Stomach acidity is decreased in pediatric patients by frequent intake of milk. When

pH environment of stomach is high, the drugs having nature of weak acids are slowl y

absorbed than the weak basic drugs. Therefore, since children tend to have decreased gastric

acidity, weak acidic drugs are absorbed more slowly and the drugs that are weak bases are

absorbed faster in pediatric patients than in adults. Bioavailability of some weakly basic

drugs such as ampicillin was found to be increased in neonates as compared to elder children

(Silverio and Poole, 1973) whereas bioavailability of weakly acid drugs such as

acetaminophen (Levy et al., 1975) and riboflavin (Jusko et al., 1976) was decreased in

neonates as compared to elder children.

2.4.5.2 Influence of age on drug distribution:

Drug distribution is a process when drug leaves the blood stream reversibly and enters

the cells of tissues and/or extracellular fluid. Distribution of drugs in the body is related to

body composition. Neonates have a much high proportion of body mass in the form of water

than elder children or adults. Total body water (TBW) in infants is about 75% of body mass

whereas it’s about 85% of body mass in small premature infants. The level of TBW gradually

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decreases with age; adult value (55% TBW) is attained by 12 years of age (Cheek et al.,

l966).

Volumes of intracellular water (ICW) and extracellular water (ECW) are also higher

in children, infants and neonates as compared to adults. Therefore, volume of drug

distribution, which is parallel to body water contents, is higher for children than adults. For

example, aminoglycosides are water soluble antibiotics and distributed initially in a volume

approximating extra-cellular fluid volume (0.2 to 0.3 L/Kg in adults as compared to 0.5 to l.2

L/Kg for neonates, infants and children). Since half-life of drugs (which is related to the time

required to achieve a desired steady state serum concentration) is influenced by volume of

distribution, it’s an important consideration in designing dosage regimen. Patients with cystic

fibrosis have an increased intravascular fluid volume as a result of cor-pulmonale; therefore

volume of distribution of both gentamicin and tobramycin is increased in those patients as

compared to normal control subjects (Kearns et al., 1982; Kelly et al., 1982). Similarly, total

body water decreases and body fat increases with age (Boreus, 1982). Therefore, lipid-

soluble drugs, such as diazepam, are less distributed in infants and children as compared to

adults, due to lack of adipose tissue and high extracellular water content in young children.

Permeability of cell membranes is greater in immature infants; therefore drug entry

into some compartments is enhanced. Brain-plasma ratios of anticonvulsant drugs are higher

in infants and children as compared to adults (Assael, 1982; Comford et al., 1983). The

important factor of influencing drug distribution is the extent of drug protein binding.

Albumin concentration directly increases with gestational age. Neonate serum contains

approximately 80% protein (Boreus, 1982). Similarly, binding affinity to albumin for many

drugs appears lower in neonates than in adults. Albumin binding of salicylate and propranolol

is low in infants as compared to adults (Morselli, 1976). This low affinity of binding may be

due to a competition for binding with endogenous substances, such as bilirubin and fatty

acids, which have higher levels in neonates as compared to adults (Broderson et al., 1983).

2.4.5.3 Influence of age on drug metabolism:

Drug metabolism is the process by which drug is chemically converted in the body to

metabolites, which may have varying degrees of activity when compared to the parent drug.

This conversion is usually enzymatic but occasionally non-enzymatic. However, drug

metabolism may change with age. The enzymatic system, which is responsible for drug

metabolism is immature (less active) at birth and its capacity increases with advancing age

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(Juchau et al., 1980; Thurman and Kaufman, 1980). This low activity may be due to low

levels of hepatic uptake, low concentrations of intracellular carrier or low levels of bile

production (Morselli, 1976; Morselli et al., 1980). However, it was found that the activity of

metabolic enzymes in neonates, infants and children is about 20 to 70% of adults, revealing

that actual enzyme activity does increase with age (Boreus, 1982).

Conjugation activity of endogenous substances and drugs is low at birth; increases to

reach adult levels (in children) by three years of age (Morselli et al., 1980; Assael, 1982).

Drugs which are mainly excreted through bile may become toxic in neonates and infants due

to low activity of the enzymatic system responsible for their detoxification and elimination.

2.4.5.4 Influence of age on drug excretion:

Drug excretion is the irreversible removal of drug (unchanged or as its metabolites)

from the body by various routes such as urine, bile (feces), respiration, milk, skin and saliva.

The most important excretory organ is the kidney which excretes non-volatile substances.

Blood flow, glomerular filtration rate, ability to concentration and acidity and tubular

function (including re-absorption and secretion) are lower in children and infants as compare

to adults. Thus, renal function in infants and children is lower as compared to adults. It was

found that the rate of glomerular filtration is low in neonates then increases gradually to adult

values by three years of age (Barnes and Goodwin, 1983). When gentamicin was applied in

premature infants, its serum concentration was high because its elimination rate was low

(Szefler et al., 1980). The excretion rate of penicillin in neonates was lower than that of

adults, because it is mainly secreted through renal tubules (Morselli, 1976). Passive tubular

re-absorption may be low in infants and neonates (Morselli et al., 1980) and their relatively

low urinary pH may also influence the rate and extent of absorption of drug. It was found that

the renal clearance of digoxin parallels the maturation of kidney function (Morselli et al.,

1980).

2.4.6 Influence of liver dysfunction on drug pharmacokinetics:

Liver is an important organ of drug metabolism. Plasma clearance of many drugs

having elimination by biliary excretion and / or biotransformation may be reduced by liver

dysfunction but it can affect plasma protein binding also which in turn influences the

distribution and elimination processes. Therefore, the pharmacokinetics of drugs being used

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to treat typhoid fever may be affected because of transient liver dysfunction due to typhoid

fever, so, in turn pharmacological or toxic effects of these drugs may also be affected.

2.4.6.1 Influence of liver dysfunction on drug absorption:

After absorption of an oral drug, it passes through the portal vein into the liver before

reaching systemic circulation, resulting in first-pass effect. The fraction of absorbed drug,

which escapes this pre-systemic elimination, is related to hepatic excretion rate and the

fraction of splanchnic blood flow passing through the functional liver. Thus, when the liver is

functioning efficiently, only a small fraction of drug reaches general circulation, whereas, in

drugs that are poorly eliminated through the liver, a large fraction reaches general circulation.

Studies have clearly demonstrated that, in cirrhotic patients, the bioavailability of an oral

drug may be increased. Examples of this increased bioavailability are lidocaine (Huet and

Villeneuve, 1983), penzocin (Neal et al., 1979), labetalol (Homeida et al., 1978) and

propranolol (Wood et al., 1978). On the other hand, liver blood flow (that carries drugs into

the circulatory system) may also affect the bioavailability of drugs. Total liver blood flow in

chronic liver disease is decreased (Branch and Shand, 1976) while it is unchanged in acute

viral hepatitis (Preisig et al., 1966). Therefore, an alteration in hepatic hemodynamic, which

may occur in liver disease, may cause changes in pharmacokinetics of drugs.

2.4.6.2 Influence of liver dysfunction on drug distribution:

Liver is the major organ for the synthesis of plasma proteins such as α1 -acid

glycoprotein and albumin onto which drugs may bind. Therefore, this binding may alter in

liver disease (which is associated with decreased concentrations of plasma proteins) resulting

in increased free drug concentration, which may increase the volume of distribution of drug.

Narang, (1985) reported that, there is significant correlation between antipyrine half-life and

serum albumin concentration. In cirrhotic patients as well as patients with acute viral

hepatitis, the binding rate of many drugs is lower than that of healthy subjects. This was

found with stavudine (Schaad et al., 1997), meropenem (Thyrum et al., 1997), lorazepam

(Kraus et al., 1978), propranolol (Branch and Shand, 1976; Branch et al., 1976; Wood et al.,

1978), diazcpam (Klotz et al., 1975; Thiessen et al., 1976), quinidine (Affrime and

Reidenberg, 1975) and phenytoin (Blaschke et al., 1975).

In addition, during liver disease, the metabolism of some endogenous substances such

as urea and bilirubin is inhibited, resulting in an increase in their blood levels. These

139

substances may compete with drugs for their binding sites (Cortes et al., 1990). However,

volume of distribution of some drugs such as tolbutamide does not change in acute viral

hepatitis because the extent of drug binding to the tissues is increased along with changes in

plasma proteins (Lewis and Jusko, 1975; Wood et al., 1978).

2.4.6.3 Influence of liver dysfunction on drug metabolism and excretion:

Biomedical and physiological problems/disturbances caused by hepatic diseases may

enhance the drug's toxicity. During early stages of the disease, metabolism of many drugs is

faster than that in normal subjects because multiple doses of ethanol induces the cytochrome

P-450 dependent monooxygenases (Vesell et al., 197l). However, with time, functional

hepatocytes convert into fibrous bands, incapable of metabolizing drugs. Such that

cytochrome P-450 isozyme and conjugation pathways may be decreased by this condition

(Paintaud et al., 1996).

Many investigators have demonstrated impaired clearance of antipyrine (Narang,

1985), theophylline (Staib et al., 1980) and clofibrate (Gugler et al., 1979) in patients of liver

cirrhosis. In contrast, clearance of drugs, such as lorazepam (Kraus et al., 1978) and

oxazepam (Shuil et al., 1976) is not affected by liver cirrhosis. It is apparent that in addition

to considerable patient variability, all drugs are not equally affected. There is selective

impairment of different routes of metabolism due to the effects of varying degrees of liver

dysfunction.

2.4.7 Influence of malnutrition on drug pharmacokinetics:

Approximately 80% of pediatric population of the world has been estimated living in

countries having limited resource and 43% of all these children have been found

malnourished (Merry et al., 1998). Malnutrition is a complex condition in which many patho-

physiological changes occur simultaneously. These changes may affect drug

pharmacokinetics. Suskind (1975), Walker (1987) and Gupta et al. (1970) reported that

malnutrition results in a decreased surface area due to impaired cell proliferation, alterations

in the intestinal flora, hypochlorhydria, delayed gastrointestinal emptying time and increased

or decreased intestinal transit time.

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Severely malnourished individuals also exhibit decreased drug oxidation, conjugation

and protein binding rates, reduced glomerular filtration rates, potentially increasing

concentrations of the parent drug or its active metabolites (Merry et al., 1998).

Krishnaswamy, (1978) reported that the liver is very sensitive to lack of dietary proteins.

Basal metabolic rate is reduced with impaired synthesis of protein (albumin) in liver during

malnutrition.

The Kidney also appears to be susceptible to changes in dietary intake in children.

Reduction in glomerular filtration and renal plasma flow are documented in malnourished

children (Alleyne, 1967). However, as a consequence of various physio-pathological

variations, there may be a wide range of changes in drug pharmacokinetics as indicated

earlier.

2.4.7.1 Influence of malnutrition on drug absorption:

The rate of absorption of oral drugs is influenced directly by changes in the

gastrointestinal tract such as pH, surface area, blood flow, flora and gut wall metabolism.

Low plasma concentrations of some drugs due to impaired absorption in malnourished

children were reported for drugs such as chloramphenicol (Eriksson et al., 1983) and

chloroquine (Walker et al., 1987). In addition, the absorption rate of tetracyclines, rifampicin

and anticonvulsants are documented to be low in malnourished adults (Raghuram and

Krishnaswarny, 1981; Polasa et al., 1984; Barro et al., 1985).

2.4.7.2 Influence of malnutrition on drug protein binding:

Malnutrition significantly alters plasma and tissue proteins synthesis. A significant

reduction in binding of several drugs has been reported in malnutrition for both adults and

children. Protein binding of quinine (Pussard et al., 1999), penicillin (Bolme et al., 1995),

antipyrine (Tranvouez et al., 1985), acetaminophen (Buchanan et al., l980b), sulfadiazine

(Mehta, 1990), tetracycline (Krishnaswamy, 1987), doxycycline, rifampicin and

phenylbutazon (Krishriaswamy et al., 1981) and chloramphenicol (Eriksson et al., 1983;

Mehta, 1983) was decreased. Volume of distribution of gentamicin, cefoxitin, paracetamol

and antipyrine dropped in malnourished children as compared to healthy children (Raghuram

and Krishnaswamy, 1981).

2.4.7.3 Influence of malnutrition on drug metabolism and excretion:

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Many studies have reported the effects of the malnutrition on elimination of drugs.

Serum concentration and elimination half-life were reported to be increased whereas volume

of distribution and clearance were decreased for many drugs such as antipyrine (Buchanan et

al., 1980a), theophylline (Eriksson et al., 1983), acetanilide (Buchanan et al., l980b),

phenobarbitone (Syed et al., 1986), chloramphenicol (Eriksson et al., 1983), paracetamol

(Mehta et al., 1985), salicylate (Buchanan et al., l980a) and sulphadiazine (Mehta., 1990). In

addition, tissue binding of drugs changed in malnourished children (Krishnaswamy, 1987).

There are also indications that protein depletion can impair plasma clearance of bilirubin,

resulting in increased levels in blood, which may compete with some drugs for their binding

sites (Flesher, 1976; Gollan et al., 1976). It was reported that serum levels of α1-acid

glycoprotein was increased in malnourished subjects and was associated with increase in the

binding rate of propranolol (Jagadesan and Krishnaswamy, 1985).

2.4.8 Influence of fever on drug pharmacokinetics:

Fever is a complex physiologic response characterized clinically by a rise in body

temperature above the normal range. However, the role of fever on drug pharmacokinetics

(absorption, distribution, metabolism and excretion) has received little attention in the clinical

literature.

2.4.8.1 Influence of fever on drug absorption:

During fever, the absorption of a drug from the gastrointestinal tract may be altered

due to changes in its physiological function and systemic circulation. Fever is accompanied

by several physiological alterations that may affect drug absorption. Gastric secretion

decreases in febrile patients (Chang, 1933) such that temperature of the body does correlate

inversely with histamine-stimulated output of peptic acid. Similar findings in dogs were

reported (Blickenstaff and Grossman, l950). Emptying of the gastrointestinal tract also slows

in febrile illnesses (Beresford et al., 197 l), which may affect the rate of absorption.

During fever tachycardia is very common and the associated increase in the cardiac

output make a contribution to an increased blood flow to gastrointestinal tract (GIT).

Increased blood flow to GIT should speed up the rate of absorption of drugs that are

administered orally. But surprisingly, profound decreased absorption of pre-labeled ferrous

ascorbate was observed in children of febrile illness or a febrile response to diphtheria-

pertussis-tetanus immunization (Beresford et al., l971).

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Similar findings were reported in the rats' injected intra-peritoneal with endotoxin

derived from E.coli (Cortell and Conral, 1976).

Additional investigations related to the influence of fever on drug absorption

including that of Van-Miert and Parra, (1970) who reported that during fever the absorption

of sulfonamide was enhanced in four of six animals studied. These findings were out of

expectation because previous studies on mono-gastric animals demonstrated the inhibition of

both the stomach secretions and the time of gastric emptying by E. coli endotoxins (Leenen

and Van Miert, 1969; Van-Miert and Parra, 1970).

In another study the effects of endotoxin induced fever was examined on the

pharmacokinetic of gentamicin in rabbits. In this research experimental model, fever

appeared to increase gentamicin absorption from intramuscular sites of injection, possibly

due to increased blood flow to the absorption sites under febrile conditions (Halkin et al.,

1981). Significantly increased absorption of oral trimethoprim was observed after the

treatment with a peptidoglycan pyrogen derived from Streptococcus pyrogenes (Lavicky et

al., 1986). Similar findings were observed in studies of rifampicin pharmacokinetics in calves

and rabbits (Lavicky et al., 1986).

2.4.8.2 Influence of fever on distribution of drug:

Many drugs in different studies have shown the inverse relationship between protein

binding and body temperature (Ballard, 1974). With highly albumin-bound drugs, both the

bound fraction and binding constant decreased with increase in body temperature. Because

unbound drug molecules diffuse freely from intravascular compartment into tissues, fever

would be expected to potentials penetration of drugs with normally high binding constants.

Serum concentration of gentamicin was decreased in dogs with fever induced/caused

by either endotoxin or etiocholanolone (Pennington et al., 1975). This may result from a

potentiating effect of fever on tissue penetration by gentamicin. Other parameters like

serum/plasma t1/2 and ClR of gentamicin were not significantly altered during fever. Several

other investigators reported an increase in volume of distribution of ciprofloxacin and

cefazolin (Beovic et al., 1999a,b), ceftriaxone (Acharya et al., 1994) and gentamicin

(Pennington et al., 1975; Halkin et al., 1981). These studies indicate that fever might enhance

drugs diffusion into peripheral compartments. However, several studies also suggested that,

this phenomenon is not universal.

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It was observed in ewes that a fraction of gentamicin residing in the central

compartment was increased as a response of fever induced by endotoxin while the gentamicin

amount was decreased in the tissues or peripheral compartments (Wilson et al., 1984).

According to another study fever causes significant increase in level of rifampin in blood and

tissues. In later experiments, fever was observed to cause in the delay of transport of rifampin

from blood or circulation into the diseased parts or organs (Leszczynska, 1979).

The disposition kinetics or pharmacokinetics of an anti-protozoan drug, imidocarb, in

febrile goats and dogs (induced by different pyrogens) was studied. It was noted that fever

significantly altered the apparent volume of distribution and systemic clearance of drugs,

which varied according to the agents used, inducing the febrile reaction (Abdullah and

Baggot, 1984).

2.4.8.3 Effect of fever on the drug biotransformation and excretion:

As indicated earlier increased cardiac output and subsequent increased blood flow to

the liver and kidney might lead one to expect an accelerated biotransformation and

elimination of drugs in the febrile subjects. However, it will be difficult to reconcile this

conclusion with the reports that bacterial endotoxin inhibits various liver functions e.g.

glucocorticoid-mediated induction of tryptophan oxygenase and phosphoenol pyurvate

carboxykinase, michrosomal cytochrome P450 and related drug metabolizing enzymes

(Bissell and Hammaker, 1976; Gorodischer et al., 1976).

Similarly, recent data suggests that pyrogenic cytokines, such as interleukins (IL)

especially IL-1 and IL-6 and interferons (IF) especially IF-alpha and T-gamma (the principle

endogenous mediators of the febrile response) are also probable mediators of the inhibitory

effects of endotoxins on hepatic function (Okuno et al., 1990). These data show that fever

inhibits rather than to facilitate the metabolism of drugs.

Few studies demonstrated the effect of pyrexia on drug biotransformation and/or

elimination (Pennington et al., 1975; Leszczynska, 1979; Demotes-Mainard et al., 1988).

These studies suggest a complex relationship exist between drug metabolism or elimination

and fever; this may be a reflection of the opposing behavior of fever on hepatic metabolic

function and hepatic blood flow.

The effects of pyrogen induced pyrexia was examined on metabolism of salicylamide

in human volunteers; it was found that fever have an association with a decreased drug's

144

transformation into its major metabolite "salicylamid glucuronide" and simultaneously

increased drug's conversion into other minor metabolites (Song et al., 1972). Therefore, in

this study as well as in two others (Van-Miert and Parra, 1970), fever was found to induce a

complex alteration in the drug biotransformation which is characterized by certain

accelerated pathways and concomitant retardation of some others.

In addition, two studies on pharmacokinetics of gentamicin (Pennington et al., 1975)

and two studies of thiophylline pharmacokinetics (Prince et al., 1989) found no effects of

fever on drugs metabolism. It was reported that fever (endotoxin induced) caused inhibited

elimination of rifampin in the rabbits (Leszczynska, 1979). Similar results were found in

studies of quinine metabolism in malarial patients' treatment (Trenholme et al., 1976), as in

studies of antipyrine metabolism in children (Forsyth et al., 1982). Also, metabolism of

phyllin, metronidazole and antipyrine were significantly decreased in malaria endotoxine-

treated rats (Kokwaro et al., 1993a,b,c).

Malarial infection caused a decrease in clearance of metronidazole and caffeine but

had no effect on antipyrine and phylline metabolism. Based on these observations, the

authors concluded that both malarial infections and fever influences the low capacity

components and the high affinity of the two-enzyme metabolism model, with little influence

on the high capacity components and low affinity.

In keeping with this theory, it was suggested that although malaria and endotoxin-

induced fever may influence P-450 dependent drug metabolism, such effects appear to be

isozyme selective (Kokwaro et al., 1993a). A similar hypothesis was proposed to explain the

elevated nitrendipine plasma level compared with unchanged bisoprolol in patients with acute

febrile illness (Soons et al., l992).

Thus, in conclusion it can be stated that fever has a complex relationship existing

between the pyrexia and drug biotransformation or elimination. This may be due to opposing

effect of fever on hepatic blood flow and metabolic functions of liver.

2.4.9 Role of gender in pharmacology of a drug:

2.4.9.1 Pharmacodynamic and pharmacokinetic:

Study of drug mechanism of action, biochemical and physiological effects of drug on

body, relationship between rate and extent of pharmacologic response and drug concentration

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is called Pharmacodynamic. So, in given concentration of blood, a drug may cause variable

response (like differences in safety/effectiveness).

2.4.9.1.1 Role of gender in disease occurrence:

Physiologic differences existing between women and men play a role in prevalence

and outcomes of the disease. For example, men are less likely to develop cataracts, thyroid

dysfunction, migraine, rheumatoid arthritis, depression, irritable bowel syndrome, hepatitis

and multiple sclerosis than women and women are less likely to develop myocardial

infarction, but within a year after MI women are more likely to be expired. On the other hand,

women have more life expectancy than men inspite of having increased susceptibility of

many diseases. Gender differences also have implications on pharmacodynamic and

pharmacokinetic of the drugs (Whitley and Lindsey, 2009).

2.4.9.1.2 Adverse effects in gender:

In the target population, knowledge of drug pharmacodynamic and pharmacokinetics

is needed for development of dosage regimens. Drug side effects are less frequent in men as

compared to women; this may be due to 2 possibilities, (1) Normalized dose taken by men is

lower than women. (2) Physiological and anatomical differences in gender may have effect

on drug pharmacokinetics. Differences in systemic clearance and distribution volume can

explain most of these changes and pre-systemic clearance may have a role in these

dissimilarities. In general men have lower drugs plasma levels, but after normalization of data

by the body weight, these differences usually are abolished or reduced, because both the

systemic clearance and distribution volume are affected by it. However in some cases these

differences persist (Carrasco and Francisco, 2011).

2.4.9.1.3 Variables effecting prescription:

Pharmacological research has greatly strengthened our understanding of different

variables affecting the drug prescription. Gender is of increasingly recognized significance

among these variables. In the United States, annually up to 7000 deaths and 5% of all hospital

admissions are because of adverse drug reactions (Khon, 2000). Identification of factors that

may pre-dispose to adverse drug reactions is important in risk management.

2.4.9.1.4 Known risk factors for adverse drug reactions:

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Known risk factors for adverse drug reactions are poly-pharmacy, liver and renal

disease, increasing age and female gender. Why female patients have this increased risk, it is

not clear, but this is due to gender related differences in pharmacodynamics,

pharmacokinetics, hormonal and immunological factors and also due to differences in the use

of drugs by men as compared to women (Carrasco and Francisco, 2011).

As compared to male patients, female has shown 1.5 to 1.7 times higher risk of having

ADRs (adverse drug reactions) [Kando et al., 1995]. Risks are higher by women than by men

and by people of color than by white people (Finucane et al., 2000).

2.4.9.1.5 Physiological and molecular factors changing drug disposition:

Sex-related differences in pharmacokinetics have been considered as an important

determinant for effectiveness (clinical) of drug therapy. The mechanistic factors resulting in

sex-specific pharmacokinetics can be divided into physiological and molecular factors.

Molecular factors involving in disposition of drug include metabolizing enzymes for drug and

transporters of drug (Meibohm et al., 2002).

Physiological factors causing sex-specific pharmacokinetics include the higher body

fat percentage, lower organ size and bodyweight, lower GFR (glomerular filtration rate),

slower gastrointestinal motility, different gastric motility and less enzymatic activity in

females as compared to males. Hence pharmacokinetics in women may be affected when it is

compared with males (Meibohm et al., 2002; Whitley and Lindsey, 2009).

2.4.9.2 Examples:

2.4.9.2.1 Women; more responsive to drugs:

Increased sensitivity and greater effectiveness of opioids,beta-blockers, typical

antipsychotics and SSRIs(selective serotonin reuptake inhibitors) are observed in females due

to pharmacodynamic differences and females are 50 to 75% more likely to develop ADRs

(adverse drug reactions) than males. Drugs causing prolong QT interval should be given

carefully in females, as females are more likely to develop torsades de pointes. Because of

high mortality rates females should take lower digoxin dosage than males (Whitley and

Lindsey, 2009).

2.4.9.2.2 Delayed gastric emptying:

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It is needed in women to increase the time interval between eating (meals) and taking

those drugs, which are absorbed on empty stomach, because of slow stomach emptying in

women. Some drugs which are cleared through urine (e-g digoxin) may need an adjustment

of dosage in females, because of slower renal elimination in females (Whitley and Lindsey,

2009).

2.4.9.2.3 Kinetics and lower body weight:

Initial drug concentrations after a bolus dose or loading dose and maximum peak

concentrations (Cmax) are dependent on the volume of distribution (Vd). Average steady-state

concentrations (Css) are dependent on clearance (ClB). For the majority of drugs, Vd and ClB

are dependent on body weight; yet few drugs are dosed based on body weight. Generally,

males weigh more than females. Therefore, based on differences in body weight alone,

females often receive higher doses which results in higher concentration and drug exposure

than males, irrespective of other pharmacokinetic differences (Carrasco and Francisco, 2011).

2.4.9.2.4 Initial researches on role of gender on bioavailability:

In 1971, antipyrine was the first drug to be kept under gender analysis for

pharmacokinetic difference (Berg, 1999). Entire elimination of this medication is by

metabolism in liver and the study confirmed that antipyrine half life was shorter in women.

The next drug to be analyzed was acetaminophen; this drug clearance was slower in women

than in men.

2.4.9.2.5 More research is needed on gender difference:

When compared with age, genetics, social habits, disease and their likely interactions,

the relative role of gender on pharmacokinetics in the clinical setting is not known

completely. But it should be studied further and considered routinely (Schwartz, 2003).

In past times, there is relative deficiency of data to evaluate gender differences in side

effects and efficacy of drug, because of underrepresentation of females in clinical trials. Fear

of teratogenicity is a major reason for female underrepresentation and women were not

included in main studies involving the drug’s efficacy. The FDA includes more women in

clinical trials since 2000. Since then, growing information about the influence of gender in

the pharmacokinetics of drugs has been published (Carrasco and Francisco, 2011).

148

It is well known that some important physiological differences exists between male

and females, which may produce differences in the pharmacokinetics of drugs, so, all

processes involving in the drug absorption, distribution, metabolism and excretion may be

changed (Carrasco and Francisco, 2011).

2.4.9.3 Absorption:

2.4.9.3.1 Routes of administration:

Drug absorption is defined as the pass from the site of administration to the systemic

circulation. Depending on the route of administration, the drug has to cross several barriers

that may contribute to reduce the bioavailability.

Gender does not significantly affect the bioavailability and protein binding after

transdermal administration of drug and the sex does not significantly affect total drug

absorption, although rate of absorption may be slightly faster in men. After oral drug

administration, bioavailability of substrates for CYP3A may be lower in men than in women

(Schwartz, 2003).

2.4.9.3.2 Factors effecting oral medication:

When the drugs are given orally, it has clearly established that peptic acid secretion,

emptying time of stomach, gastrointestinal (GIT) blood flow; presystemic metabolism and

transporters activity influence the absorption of drugs. Although there is little information

concerning changes due to gender in such factors, it has been established that changes in the

bioavailability of several substances may occur (Walle et al., 1985; Timmer et al., 2000).

Difference in stomach pH, GIT (gastrointestinal) motility and enzymes activity affect

the drug absorption after oral administrations. Men secrete more gastric acid and have faster

gastrointestinal (GIT) transit times than women (Fletcher et al., 1994).

It has been reported that some hormones may change secretion of gastric acid.

Therefore stomach pH and additionally, a slower emptying time of stomach is present in

females (Gandhi et al., 2004). Such changes results in significant delay of the onset of

effectiveness of enteric-coated dosage forms and drug solubility and dissolution rate may be

modified (Donovan, 2005).

149

However, contradictory results have been published, since there is evidence indicating

that no change in the pharmacokinetic parameters is observed in several studies. As it can be

seen, it is not possible to predict that in which cases differences among men and women, in

the absorption of enteric coated formulations will be present, since several factors may

contribute to the possible gender differences and it is a quite difficult to establish if

differences are due to these factors.

Other factor that may give some contribution to sex related differences in drug PK

(pharmacokinetics) is the gastrointestinal blood flow (Fletcher et al., 1994). It has been

described that usually women have lower organ blood flow. The theoretical consequence of

this diminished flow may be a slower rate and probably lower extent of drug absorption

(Schwartz, 2003).

Alcohol absorption and bioavailability differs among women and men. Men will have

a lower alcohol level in blood than women after consumption of the same ethanol

concentration; this is because of increased GIT (gastrointestinal) enzyme (alcohol

dehydrogenase) activity, which results in faster degradation of ethanol in males (Baraona et

al., 2001).

2.4.9.4 Distribution:

Gender related differences in pharmacodynamic and pharmacokinetic result in

different responses to medications. More information is available on differences in

pharmacokinetic.

2.4.9.4.1 Factors influencing distribution:

It is well known that gender differences in the composition of body are present. Some

of these differences are due to difference in composition of body, fat% of body, BMI (body

mass index), volume of plasma, plasma protein-binding capacity and organ blood flow

(Beierle et al., 1999). All these stated factors affect the distribution of drug in the body

(Schwartz, 2004; Schwartz, 2007). It has been described that men have higher average body

weight, lower body fat%, larger average volume of plasma and higher average blood flow of

organs than women (Beierle et al., 1999; Pleym et al., 2003).

2.4.9.4.1.1 Body size and body fat:

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There is smaller volumes of distribution and slower total clearance of many drugs in

women as compared to men due to differences in body sizes and on average females are

smaller than males. Lipophilic drugs may have higher volumes of distribution in females due

to higher fat% of body. This high body fat% persists until older ages (Schwartz, 2003). Males

are heavier with larger viscera (organs) and higher body mass index (BMI) than females

while doing calculation of bolus or loading dose, such differences must be considered

(Schwartz, 2004). To avoid unnecessary ADRs (adverse reactions), females should take

smaller doses (Schwartz, 2004; Schwartz, 2007).

2.4.9.4.1.2 Protein binding:

As a result of these disparities, important distribution differences between genders are

observed (Pleym et al., 2003). Other factor that may cause contribution to sex related

differences in drugs distribution is the protein binding, as sex hormones concentration affects

main groups of protein which are responsible for binding of the drugs. Therefore, changes in

distribution may occur between genders and during the menstrual cycle (Succari et al., 1990;

Walle et al., 1994).

2.4.9.4.1.3 Solubility:

2.4.9.4.1.3.1 Drugs; having water solubility:

As a general rule, water-soluble compounds are more widely distributed in men than

in women, since water content of men, normalized by the body weight, is about 15 to 20%

higher than women. Some examples of this situation are fluconazole (Carrasco and Francisco,

2011) and metronidazole (Carcas et al., 2001), in which distribution volume is bigger in

males as compared to females and such differences remain, although normalization by weight

is carried out (Carcas et al., 2001; Carrasco and Francisco, 2011).

Hydrophilic substances, such as alcohol (Schwartz., 2004) distribute into higher

volumes in men, causing lower initial concentrations in plasma and lower effects.

2.4.9.4.1.3.2 Drugs dissolved in lipids:

On the contrary, hydrophobic drugs are more widely distributed in women, due to

higher fat percentage. However, most of the times, changes in volume of distribution of the

drug are completely abolished when the parameter is normalized by the body weight. But the

main concern is that usually, dosage regimens employed for most of the currently used drugs

151

are not undergone normalization by individuals body weight, this situation may explain, at

least in part, the increased concentrations and therefore more frequency of side effects

observed in women.

Because the females have higher body stores of fat than males, which may results in

larger volume distribution of drug, which depends on hydrophobic and hydrophilic

characteristics of drugs. Because of having smaller volumes of fatty tissue in males than

females, lipophilic drugs such as benzodiazepines (diazepam) and neuromuscular blockers

(Xue et al., 1997) have shorter duration of action in males. As well as males are 30% less

sensitive to neuromuscular blocking agents (rocuronium) and need 22% larger doses than

females (Xue et al., 1997).

2.4.9.5 Metabolism:

2.4.9.5.1 Metabolic enzymes:

Drugs metabolism by liver occurs through Phase I, Phase II metabolism and by

combined conjugation and oxidative processes. Phase 1 includes reduction, hydrolysis and

oxidation through cytochrome P450's (2E1, 1A, 2D6,). Phase II includes conjugation,

glucuronidation, dehydrogenases, methyltransferases and glucuronyltransferases. These

processes are mostly cleared slower in females when compared to males (mg/kg basis). But

metabolism through N-acetyltransferase, CYP2C19, CYP2C9 and p-glycoprotein substrates

are more likely to be same in males and females. On the other hand, a number of CYP3A

substrates clearance seems to be a little bit slower (mg/kg) in men than in women (Schwartz,

2003). Some studies show that activity of CYP3A is higher in females compared to males

(Greenblatt and Lisa, 2008).

2.4.9.5.2 Phase-I reactions:

Many drugs are metabolized via phase-I reactions in liver and initial step (phase) of

metabolic process hydroxylates, reduces or oxidizes compounds via cyto-P450 (cytochrome)

system. Coumadin (warfarin) is amongst one of the drugs which shows different requirement

of dosage depending on gender. Sources show that females require between 2.5 mg and 4.5

mg (Whitley and Lindsey, 2009) less warfarin per week than men.

2.4.9.5.3 Phase-II reactions:

152

Polar conjugates of phase-I compounds (metabolites) or parent medications are

produced by phase-II metabolic processes for excretion through kidney. It occurs via

methylation, glucuronidation, acetylation or sulfation. These phase-II metabolic reactions are

usually faster in males, resulting some drugs to excrete faster; these drugs includes

caffeine (Schwartz, 2004), digoxin (Yukawa et al., 1997), fluorouracil (Schwartz,

2004), levodopa (Schwartz, 2004), mercaptopurine (Schwartz, 2004) and propranolol

(Inderal) [Walle et al., 1985; Schwartz, 2004].

2.4.9.6 Excretion:

Excretion of drugs can be carried out by several pathways; however, renal excretion is

one of the most important routes of drug excretion.

2.4.9.6.1 Filtration:

GFR (Glomerular filtration rate) is higher in males compared to females, moreover,

after normalizing GFR by the body size, a 10% difference remains (Gross et al., 1992) and

therefore, renal clearance may be diminished for a wide variety of drugs.

2.4.9.6.2 Re-absorption and secretion:

Concerning other mechanisms involved in the renal clearance, it has been reported

that sex-related differences in the tubular secretion and re-absorption present. It has been

established that clearance of taurocholate is increased in female rats when compared with

male rats, indicating an increased re-absorption process in females (Kato et al., 2002;

Schlattjan et al., 2005). Moreover organic anions excretion through urine in female rats is

increased in comparison with male rats (Kato et al., 2002, Kudo et al., 2002, Cerrutti et al.,

2002) indicating that renal clearance of organic anions may be increased in females.

2.4.9.6.3 Body weight:

As tubular re-absorption, tubular secretion and glomerular filtration are likely to be

slower in women than in men whether consideration done on basis of total body weight or on

mg/kg. So, in general renal clearance observed in women is lower than the values obtained in

men. Probably this may be due to the increased GFR observed in men that seems to have the

major role in the renal clearance of drugs. Sex and in some cases weight are incorporated as a

factor in algorithms using for estimation of GFR (Schwartz, 2003).

153

2.4.9.6.4 Physiological conditions:

There are several physiological conditions that are different between genders and that

are reflected in dissimilarities in the oral pharmacokinetics of drugs. Probably the two

parameters that are more affected by this situation are volume of distribution and systemic

clearance. Studies showed that main differences at molecular level in mammalian genders

exist which involved in renal function and metabolism of medications (Rinn et al., 2004).

2.4.9.6.5 Medicines:

Slow clearance of those drugs is seen in females which are eliminated unchanged

through urine (Schwartz, 2004) e-g, digoxin (Yukawa et al., 1997) and methotrexate

(Schwartz, 2004), both are excreted mostly through urine and having 13 and 17% faster

elimination in men, respectively. Many other drugs like cephalosporins (Schwartz, 2004),

aminoglycosides (Schwartz, 2004) and fluoroquinolones (Schwartz, 2004) have slower renal

elimination in females. So, these drugs should be received by females in lower doses.

2.4.9.7 Few examples about role of gender:

2.4.9.7.1 Pantoprazole, levofloxacin and losartan:

In order to contribute to the establishment of sex related differences in the PK

(pharmacokinetics), oral pharmacokinetics of three medications, pantoprazole, levofloxacin

and losartan were evaluated in women and men (Carrasco and Francisco, 2011).

2.4.9.7.1.1 Pantoprazole:

In the first study, oral pharmacokinetics of enteric coated formulation of pantoprazole

was evaluated in 52 healthy volunteers (26 females and 26 males). It was noted that high

levels in plasma were achieved in females, but after normalization of data by administered

dosage, these differences were disappeared; this was reflected in differences in several

pharmacokinetic parameters, Cmax, AUC and ClB. After normalization of values by the

individuals' body weight, it can be seen that volume of distribution is slightly lower in

women. These results seem to indicate that volume of distribution is reduced about 20% in

females as compared to males; this may be due to the body water differences between women

and men.

2.4.9.7.1.2 Levofloxacin:

154

In the second study, the oral pharmacokinetics of levofloxacin was evaluated in

female and male subjects. It was observed that achieved levels in plasma are about 20%

higher in women, but the difference completely disappeared when data were normalized by

the individual weight.

2.4.9.7.1.3 Losartan:

In the third study, oral pharmacokinetics of losartan was evaluated in 26 females and

26 males. It was observed that achieved levels in plasma are higher in females as compared to

males. After normalization of pharmacokinetic parameters by the body weight, an increased

clearance was observed in women.

2.4.9.7.2 Clindamycin:

Antimicrobial agent clindamycin is processed (metabolized) via CYP3A4. Drugs

pharmacokinetics processed via this pathway may be influenced by gender. But, there is lack

of information (data) about pharmacokinetic differences of clindamycin in males and

females. Gender difference in pharmacokinetics of clindamycin after oral administration was

evaluated. Oral dose of 600 mg clindamycin was taken under fasting conditions by 24

volunteers (11 males and 13 females) and at specific times in next twelve hours,

concentrations in plasma were noted. High levels in plasma were seen in females, however

after normalization of dosage by individuals' body weight, such differences were not seen,

which showed that there is no significant role of sex in the pharmacokinetics of clindamycin

(Carrasco et al., 2008).

2.4.9.7.3 Moxifloxacin:

Sex or age related pharmacokinetic differences are not exhibited by moxifloxacin. At

1st day after oral administration of 200-400 mg dose produces an effective antibiotic

concentrations (Sullivan et al., 2001).

2.4.9.7.4 Cefepime:

Cefepime belongs to broad-spectrum, fourth-generation cephalosporin. As

distribution volume and clearance of this drug shows no valuable differences among men and

women, so, for a given infection treatment, cefepime dosage should not be dependent on sex

(Barbhaiya et al., 1992).

155

As it can be seen, it is not possible to anticipate gender-related changes in drugs

pharmacokinetics after oral administration and therefore, case by case evaluation is important

in order to establish the adequate dosage regimen according to body weight and gender.

Although in most of the cases increased levels are seen in females as compared to males and

such difference is mainly due to the administration of higher normalized doses in women

(Carrasco and Francisco, 2011).

2.4.9.7.5 Cefuroxime:

In beagle dog, after intravenous (IV) infusion of 2 forms of this antibiotic i.e. cefuroxime

sodium and cefuroxime lysine showed insignificant difference (P > 0.05) in genders of dogs

and in the weight and age for different doses, this was studied in a population

pharmacokinetic and bioequivalence modeling. However cefuroxime lysine relative

bioavailability showed a significant difference (i.e. 𝑃 < 0.05) between men and women and it

was 1.05±0.18 (0.71-1.42). Therefore, in terms of extent and rate of absorption, both forms of

antibiotics (cefuroxime sodium and cefuroxime lysine) were bioequivalent. As well as among

these 2 antibiotics, there was found no sex related difference in the PK (pharmacokinetic)

data (Zhao et al., 2012).

2.5 Pharmacokinetic studies of cefixime:

Pharmacokinetic studies of cefixime are usually performed by microbiological assay

procedure and by HPLC. Both these methods are developed for the analysis or estimation of

concentration of cefixime in blood (plasma and/or serum), urine, bile and other biological

fluids (Falkowski et al., 1987; Neu, 1988).

2.5.1 Bioavailability of cefixime:

A number of pharmacokinetic studies of cefixime have been conducted in both

healthy and diseased children, adults and elders (Faulkner et al., l987b). The

pharmacokinetics of cefixime in healthy children following oral doses of l .5 or 3 mg/Kg of

the body weight was studied. They found the mean peak serum concentrations of cefixime to

be 0.64 and 1.l5 µg/ml after 4 hours of giving 1.5 and 3 mg/Kg, respectively (Motohiro et al.,

1986).

In another study, a single dose of oral cefixime of l .5 and 6 mg/Kg of body weight

was administered into healthy children. The mean peak concentrations of cefixime were l .34

http://www.hindawi.com/70632126/

156

and 2.5 µg/ml and the mean half-lives were 3.53 and 6.77 hours (for the dose of l .5 and 6

mg/Kg), respectively (Miyazaki et al., 1986).

Pharmacokinetics of cefixime in oral form was studied in healthy children in two

single doses of 3 and 6 mg/Kg. The mean peak concentrations of cefixime were l.7 and 2.72

µg/ml for these doses, respectively, attained at 4 hours after dosing. The elimination half-

lives were 3.09 and 3.11 hours for 3 and 6 mg/Kg, respectively (Iwai et al., 1986).

Another study was conducted in children with infection. Cefixime was administered

orally in single dose of 1.5 and 6 mg/Kg. The peak serum concentrations of cefixime were

0.65 µg/ml at 2-3 hours and 3.33 µg/ml at 4 hrs and the elimination half-lives were 2.4 and

2.5 hrs for the low and the high dose, respectively (Kurashige et al., l986).

Another study on cefixime pharmacokinetics was conducted in pediatric patients after

an oral dose of 1.5, 3 and 6 mg/Kg body weight (Fujii, 1986), the mean serum concentrations

at 12 hours were 0.2, 0.4 and 1.3 µg/ml, respectively; and the half-lives were ranging from

2.7 to 3.9 hours. Another study conducted in (US) pediatric patients using dose of 4, 6 and 8

mg per Kg body weight. The mean serum concentrations at 3.5 hour were 2.44, 4.07 and 3.91

µg/ml, respectively (Faulkner et al., l987b).

Cefixime was administered to healthy male adults (in a randomly ordered, double

blinded study with one week intervals between doses of 50 mg, 100 mg, 200 mg and 400

mg). Mean serum concentrations of cefixime were l.02 µg/ml, 1.46 µg/ml, 2.63 µg/ml and

3.85 µg/ml for doses of 50 mg, 100 mg, 200 mg and 400 mg, respectively; and times to

maximum peak were 2.7, 3.4, 3.9 and 4.3 hours for the respective doses. After 12 hours of the

drug administration, the mean concentrations of cefixime in serum were 0.33, 0.72 and l.13

µg/ml for doses of 100 mg, 200 mg and 400 mg per Kg body weight, respectively (Brittain et

al., 1985).

Faulkner et al. (l987b) studied the pharmacokinetics of cefixime after multiple oral

doses administered once or twice daily. Blood samples were collected on l, 8 and 15 days.

Mean peak concentrations were similar on all days with mean peak concentrations of l.64 to

l.8l µg/ml for the dose level of 200 mg twice daily and 2.64 to 2.96 µg/ml for the dose level

of 400 mg once a day. The bioavailability of cefixime was about 45% for a single oral dose

of both 200 and 400 mg. Extent of bioavailability was 26 µg/ml. hour for 200 mg oral

solution in healthy adults (Faulkner et al., l987a).

157

The serum t1/2 of cefixime in healthy subjects averages 3-4 hours but in some normal

volunteers it may range up to 9 hours and this plasma half life is independent of drug dosage

form. In elderly patients, at steady state, average AUCs are about 40% more than the average

AUCs at steady state, in other human healthy adults (Baltimore, 2005).

2.5.2 Distribution of cefixime:

Protein binding of cefixime is about 70% (Bialer et al., 1986). Volume of distribution

of cefixime is not concentration dependent and was ranged from 0.5 to 26 mg/L. The free

fraction of cefixime in plasma tended to increase with decreasing renal function but this rise

did not reach statistical significance (Faulkner et al., l987b). After absorption of cefixime, it

is distributed into all tissues including the respiratory tract and inflammatory exudates

(Grellet et al., 1989) whereas it penetrates to a lesser extent into aqueous humor and tonsils of

the children (Begue et al., 1989). Cefixime readily penetrates into cerebrospinal fluid (CSF)

of children with meningitis whereas penetration into CSF of healthy children is poor (Nahata

et al., 1993). Following 100 mg administration of oral cefixime to the pregnant women,

plasma concentrations were in between 0.18 and 0.8 mg/L at 0.5 to 5 hours after ingestion.

Through-out this period, the concentration in serum of umbilical cord was about 15% to 30%

of that in the maternal plasma (Takase et al., 1985). Serum or plasma protein binding is not

dependent of the concentration and the bound fraction of drug is about 65%. In a multiple

dose study of a research formulation that was less bioavailable than suspension or Tablet, a

little accumulation of drug was found in serum or urine after 14 days dosing (Baltimore,

2005).

2.5.3 Elimination of cefixime:

Cefixime has affinity to reach in renal parenchyma. Penetration of cefixime in renal

parenchyma does not much vary as compare to cortex and medulla. The result showed that

cefixime concentration has rapidly decreased in serum as compare to tissue concentration of

cefixime (Leroy et al., 1995). Decreased creatinine clearance caused an increase in

elimination half-life and decrease in apparent total body clearance (renal and non-renal) and

protein binding.

Cefixime is excreted mainly in the bile (60%) as unchanged form and also by the

kidney (40%) partly (Barre, 1989). Low urinary recovery rate and the high cefixime

concentration in the bile and in gallbladder tissues indicate extensive elimination of this drug

158

by liver (Tanimura et al., 1985). The elimination half life varies between 3 to 4 hrs (Brittain

et al., 1985; Saito, 1985; Faulkner et al., l987b). Total systemic clearance of the drug was

about 4.41 ml/min, following single dose of 200 mg intravenous cefixime in healthy human

subjects with renal clearance of about 40% (Faulkner et al., 1988). About 50% of the

excretion of absorbed dose occurs in the urine in unchanged form in 24 hours. It was found in

animal studies that cefixime is also excreted in bile in excess of the 10% of the dose

administered (Baltimore, 2005).

2.5.4 Biliary excretion of cefixime:

The main pharmacokinetic characteristics of cefixime in healthy subjects are

prolonged elimination t1/2 and extra-renal processes for drug clearance, as clearance by renal

pathway is about only 40% of the total systemic clearance (Faulkner et al., 1988).

For this cephalosporin, no drug metabolite which is biologically active has been found

in serum/plasma, biliary or urinary excretion. Biliary excretion of cefixime was analysed in

10 patients with T-tube drainage of common bile duct after cholecystectomy. Cefixime's

maximum concentration reached in the bile was 56.9±70 mg/liter following a single oral dose

of 200 mg, which was about 20 times greater than the peak serum concentration, i.e. 2.3±0.85

mg/liter. Results showed that an oral dose of 200 mg of cefixime provided the consistently

higher drug levels in the bile than MICs for the most frequently recovered members of the

family Enterobacteriaceae in biliary tract infections and these drug levels were maintained for

over 20 hrs after dosing. Clinical trials are required to find out usefulness of this

cephalosporin in both the prophylaxis and treatment of infections of the biliary tract

(Westphal et al., 1993).

2.5.5 Penetration and bactericidal action of cefixime in the synovial fluid:

Cefixime is indicated to treat otitis media, upper and lower RTIs and infections of the

urinary tract when these infections are caused by susceptible organisms (Goto et al., 1985).

The role of cefixime in prophylaxis and treatment of joint infections was not studied till 1996.

A study was conducted to verify the concentration of cefixime in the joint fluid following

oral administration of the agent. The penetration of oral cefixime was examined into the

synovial fluids of 16 patients (mean age, 50.6 years) who underwent joint taps for rheumatic

noninfectious disorders. The patients were administered a single 400 mg dose. Cefixime level

in serum and in joint fluid samples were measured by HPLC and the bactericidal activities of

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these fluids against three isolates each of Haemophilus influenza and Escherichia coli were

examined. The highest concentrations in serum and synovial fluid were achieved 4 hr

following drug intake, the mean values being 2.8 and 2.03 mg/ml, respectively. Effective

bactericidal activities (bactericidal titer>1:2) against E. Coli and H. Influenza were

demonstrated in serum and joint fluid up to 10 hr following oral intake of cefixime. These

results suggest that cefixime penetrates well into joint fluid, achieving levels above the MIC

for E. coli lasting as long as 10 hr and levels above the MIC for H. influenza lasting up to 24

hr after administration. Good bactericidal activity against susceptible bacterial isolates was

observed for at least 10 hr after dosing. So, in this study conducted to check the cefixime

ability to reach synovial fluid, the conclusion was that cefixime can penetrate well in synovial

fluid and after 10 hours administration of cefixime it has good bactericidal activity (Somekh

et al., 1996).

2.5.6 Influence of disease state on cefixime pharmacokinetics:

2.5.6.1 Hepatic dysfunction:

The pharmacokinetic studies of cefixime were conducted in hepatic patients with

varying degrees of disease. The pharmacokinetics of cefixime was studied in-patient with

severe impairment of liver function. They reported that the Cmax and AUC were did not differ

by degree of impairment. The time for maximum concentration was prolonged. The volume

of distribution was increased possibly due to ascites and hypoalbuminemia (Singlas et al.,

1989).

2.5.6.2 Renal dysfunction:

Cefixime may be given in state of renal impairment. In patients having 60ml/min or

more creatinine clearance, normal dose and schedule may be employed. Total 75% of the

standard dosage may be administered at the standard dosing interval to the patients having

creatinine clearance 21 to 60 ml/min or to the patients who are on hemodialysis (i.e. 300 mg

daily). For the patients with clearance < 20 ml/min or for patients who are on ambulatory

peritoneal dialysis continuously, half (50%) of the standard dosage is recommended at

standard interval of dosing (i.e. 200 mg a day). Both peritoneal dialysis and hemodialysis do

not remove the significant amount of drug from body (Baltimore, 2005).

Cefixime pharmacokinetic studies have been conducted in renal patients with varying

degrees of dysfunction or impairment and in subjects undergoing peritoneal or hemodialysis

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(Guay et al., 1986). Single dose of 400 mg were administered to these patients. The

absorption was delayed to 4 hours. Peak serum drug concentration in patients having

creatinine clearance of 41-60 ml/min averaged 7.48 µg/ml and it was 9.5 µg/ml in patients

having creatinine clearance in range of 5-20 ml/min. The t1/2 increased from 3 hours in

normal subjects up to 6 hours in patients with clearance of creatinine ranging 41 to 60 ml/min

and to 11.5 hours in individuals with clearances of 5 to 20 ml/min.

Pharmacokinetic studies of oral cefixime were studied in children having urinary tract

infection after single dose of 8 mg/Kg of the body weight. The mean peak drug concentration

in plasma was 4.04 µg/ml achieved at 3.2 hours after dosing. The mean area under time

versus drug concentration curve was 33.07 µg.hr/ml and the mean elimination t1/2 was 3.91

hours. The mean total apparent clearance was 4.74 ml/min/kg (Mamzoridi et al., 1996). In

addition, the effect of renal dysfunction on cefixime disposition after single oral dose of 200

mg was also studied. In ureaemic patients, maximum concentration and time for maximum

concentration were slightly increased than control and the half-life was also increased up to

12-14 hours; the apparent volume of distribution was decreased (Dhib et al., 1991).

2.5.7 Bioequivalence and pharmacokinetic parameters of cefixime:

Various bioequivalence studies of cefixime have been reported in literatures which

show the existence of bioequivalence in cefixime products of different manufacturers and

different dosage forms.

2.5.7.1 Bioavailability study of cefixime:

As oral cephalosporins are inactivated by gastric acid and due to their hydrophilicity

they are unable to traverse the mucosal barrier of small intestine, so, these are the reasons due

to which cephalosporins have poor absorption generally. However newer oral cephalosporins

have quite varied oral absorption. Although 400 mg capsule cefixime has lower urinary

excretion, the absolute bioavailability is higher, 40% to 52% (Brogden and Campoli-

Richards, 1989).

After a 400 mg dose, maximum plasma concentration of cefixime in adults generally

ranges from 3 to 5 mg/L (Brogden and Campoli-Richards, 1989). Cefixime is slowly

absorbed amongst the newer oral cephalosporins; with peak absorption after two hours.

Penetration into the tissue fluids exceeds 130%. The elimination t1/2 is generally about 3

hours and it is prolonged in the patients having impaired kidney function e.g. in patients who

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have creatinine clearance less than 20 ml/min (Low, 1995). Protein binding capacity for

cefixime is about 65% (which is concentration independent). Biotransformation or hepatic

biotransformation studies show that urinary excretion (unchanged) in 24 hr is approximately

50%.

These findings support the usage of this 3rd generation agent once a day or twice daily

for lower respiratory tract and other infections (Low, 1995).

Pharmacokinetic of a broad-spectrum cephalosporin, oral cefixime was assessed in 12

healthy subjects after 50, 100, 200 and 400 mg in single doses. The values of Cmax were 1.02,

1.46, 2.63 and 3.85 µg/ml after the four respective doses. At 12 hours, respective mean serum

levels were 0.16, 0.33, 0.72 and 1.13 µg/ml. The value of Vd averaged 0.1 L/kg body weight

and the t1/2-β was 3 hours for all the doses. The AUCs were 7.01, 11.4, 22.5 and 36.4

µg.hr/ml, respectively, for the four doses. Serum ClB averaged 0.4 mg/min/kg and mean

urinary recovery for the four respective doses was 21%, 19%, 20% and 16% in 24 hour

(Brittain et al., 1985).

2.5.7.2 Different brands of cefixime:

Comparative bioavailability of two cefixime oral formulations was evaluated in total

24 healthy males. The trial was planned as a randomized, open, two-sequence, single-blind

and two-period crossover study. In fasting condition, each subject received 400 mg cefixime

(reference and test formulation) Tablet as single oral dose, on two treatment days. Wash out

duration was of one-week. A sensitive and rapid HPLC technique with UV detector was used

to analyse plasma concentration of cefixime. Pharmacokinetic parameters used were AUC(0-

infinity), AUC(0-24), t1/2, Cmax and Ke. Mean AUC(0-infinity) was 45008.7±10989.9 and

45221.3±2155.7 ng.hr/ml and Cmax was on average 4746.9±1284 ng/ml and 4726.3±1206.9

ng/ml for test and the reference products, respectively. Statistical difference was not seen for

area under time-plasma drug concentration curve and for Cmax of both the reference and test

formulations. The 90% calculated confidence intervals, by ANOVA, for the mean

test/reference ratios of AUC(0-24), AUC(0-infinity) and Cmax of cefixime were in their

bioequivalence range (94%-112%). So, both formulations were bioequivalent to each other

(Zakeri et al., 2008).

A study was conducted on Comparative bioavailability of cefixime (Winex vs

Suprax) suspension (100 mg/5ml) in male healthy volunteers. Suprax was used as reference

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product. Twenty four healthy male volunteers received single dose of 200 mg of both brands

orally, on two treatment days with an overnight fasting of ten hours and washout period was

of one week. A Balanced and randomized two-way crossover design was employed. Blood

samples were withdrawn for 16 hours at different time intervals. A sensitive HPLC assay was

applied to analyze cefixime concentration in serum/plasma.Pharmacokinetic parameters were

calculated by non-compartmental standard method. The determined parameters were T max,

AUC(0-infinity), AUC(0-t), Kel, Cmax, t1/2 and Cmax/AUC(0-infinity). The 90% confidence intervals of

mean values of pharmacokinetic parameters such as, AUC(0-t), AUC(0-infinity), Cmax and

Cmax/AUC(0-infinity) were within 80 to 125% which was an acceptable range of bioequivalence

(using log-transformed data). The 90% confidence intervals calculated by ANOVA for the

mean test/reference ratios of AUC(0-t), AUC(0-infinity), Cmax and Cmax/AUC(0-infinity) were 88.93-

107.10%, 89.09-107.11%, 89.63-108.58% and 96.85-105.29%, respectively. Both the test

formulation (winrex) and reference formulation (suprax) were bioequivalent (Asiri et al.,

2005).

Bioequivalence of two cefixime capsule 100 mg brands (Alpha-cefixime and Suprax)

has been investigated in 24 healthy volunteers in Korea, divided into 2 groups. A randomized

cross-over study was employed. Between the doses, the washout period was one week.

Cefixime concentrations in plasma, collected at predetermined intervals of time, were

analyzed by HPLC using UV detector. Bioequivalence parameters calculated were AUC (t),

Tmax and Tmax and for statistical analysis of these parameters ANOVA method was employed.

According to the results the differences in AUC(0-t), Cmax and Tmax of these two products were

-3.91%, -2.23% and -3.18%, respectively, when they were calculated against reference drug.

All the parameters fulfilled the KFDA criteria for bioequivalence, which indicated that

Alpha-cefixime capsule (Alpha Pharmaceutical Co.) and Suprax capsule (Dong A.

Pharmaceutical Co.) were bioequivalent (Choi and Jin, 2007).

In study of Bioequivalence of cefixime, two brands of cefixime capsule 200 mg were

given as single administration as test and reference to 20 healthy males in randomized

crossover design. Cefixime serum concentration was determined by high performance liquid

chromatography and bioassay. Program 3P97 was used for analysis of data and calculation of

data was done on the basis of one-compartment model. Pharmacokinetic parameters which

were determined after HPLC analysis for both reference and test capsules were as follows:

Cmax (2.317±0.536 and 2.287±0.492 mg.L-1); Tmax (4.1±0.7 and 4.3±0.7 hr); AUC(0-16)

(17.251±5.087 and 16.954±4.536 hr.mg.L-1); AUC(0-∞) (l8.386±4.559 and 18.138±3.931

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hr.mg.L-1). The pharmacokinetics parameters calculated after bioassay for test and reference

products were as follows: Cmax (2.437±0.495 and 2.361±0.435 mg.L-1); Tmax (4.13±0.65 and

3.90±0.45 hr); AUC(0-16) (18.741±3.931 and 18.064±3.350 hr.mg.L-1); AUC(o-∞)

(20.109±4.497 and 19.403±3.693 hr.mg.L-1); respectively. No significant difference was

found there. Relative bioavailability of group determined by HPLC and bioassay was

101.53±18.21% and 103.30±15.78%. All the results showed that both preparations were

bioequivalent. HPLC and bioassay methods both were interrelated (Ying et al., 2003).

2.5.7.3 Different dosage forms of cefixime:

Study on bioavailability and bioequivalence of cefixime in healthy volunteers was

conducted. Cefixime 200 mg Tablet and capsule (cefspan) was given as single oral dose to 20

healthy volunteers in randomized crossover study. Concentration of cefixime in plasma was

determined by HPLC. Computer program 3p97 was used for calculation of pharmacokinetics

parameters and bioavailability. The linear range of cefixime was 0.1-5.0 µg/ml (r=0.9993).

The values of t1/2ke were (4.98±0.58) hr and (5.28±0.77) hr; of Tmax were (4.7±0.6) hr and

(4.6±0.9) hr andof Cmax were (3.38±0.9) μg/ml and (3.29±0.87) μg/ml for cefixime Tablets

and cefixime capsules, respectively. The relative bioavailability of cefixime Tablets to

cefixime capsules was 102.8±19.7%. These results indicated that two preparations were

bioequivalent (Lan-Ying et al., 2004).

In a bioequivalence study of Tablet and sachet of oral cefixime 200 mg as single

doses in 18 healthy human volunteers (males), obtained data demonstrated that two

formulations were bioequivalent. Reference formulation (Tablet Oroken 200 mg) and test

formulation (novel Orokensachet 200 mg), were tested in crossover study. Statistical

differences were neither observed for Cmax nor for AUC at confidence interval of 90% in-

between mean Cmaxand mean AUC of the sachet and Tablet. So, both preparations were

within bioequivalence interval (0.8-1.25). No evidence was found for difference in-between

t1/2 (serum half-life) and Tmax (time to reach Cmax) of two formulations. Moreover, for both

formulations, unchanged cefixime in comparable amounts were eliminated by urine, over

same time frames. Biological and clinical tolerability for these both formulations were also

excellent. Result in this study shows bioequivalence for Tablet and sachet forms of cefixime

in terms of rate and extent of absorption (bioavailability). If patient is unwilling or unable to

take cefixime Tablet, the formulation of cefixime sachet may be of considerable value for

him (Evene et al., 2001).

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A comparative pharmacokinetics study of domestic and imported cefixime in

volunteers in 3 dosage forms (fine granules, capsule and Tablet) were performed in 30

volunteers. There was no statistical difference in the results of domestic and imported

cefixime in different dosage forms for following listed mean parameters: Cmax 2.17-2.62

μg/ml, Tmax 3.4-4.6hr, AUC 25.8-29.5μg.hr/m1, t1/2ke 3.50-4.43hr, MRT 7.47-8.15hr.

Bioassay technique was used for determination of plasma level of drug. From the results it

was concluded that there was no significant difference between domestic and imported

cefixime dosage forms (Jieying et al., 1996).

2.5.7.4 Role of diet (fasting and non-fasting conditions):

Food has been shown to have a minimal effect upon peak serum level with 4.22 µg/ml

achieved after ingestion of 400 mg with food and 4.24 µg/ml when 400 mg was ingested

while fasting. There was prolongation in the time to achieve maximum absorption from 3.78

hours to 4.8 hours with food. However, AUC were statistically not different, 32 and 30.8

µg.hr/ml, respectively (Faulkner et al., l987a).

Pharmacokinetic profile of cefixime was studied in healthy volunteers in fasting and

non fasting state along with detection of cefixime in serum by HPLC method. Cefixime200

mg was given to eight healthy volunteers as single oral dose, in fasting and non-fasting (after

meal) state, the mean maximum concentration in plasma were 2.7±0.9 and 1.7±0.4 mg/L, the

mean t1/2ke were 3.7±0.4 and 3.3±0.7 hours. The mean AUC were 25.4±8.5 and 13.9±4.0

hr.mg/L while 23.7±7.5% and 13.6±4.5% of the drug were excreted via urine within 24hr.

The mean serum concentrations at 12 hr were 0.83±0.26 and 0.45±0.18 mg/L respectively.

The pharmacokinetic parameters of cefixime among volunteers were significantly different

such as of Cmax, AUC and urinary excretion rates in fasting and after meal state. HPLC

method employed for cefixime detection was accurate and reproducible. The serum drug

concentrations analyzed by HPLC were highly correspondent with that of obtained by

bioassay (Yaoguo et al., 1994).

2.5.7.5 Comparative pharmacokinetic:

In a comparative pharmacokinetic study of orally administered ceftibuten, cefixime,

cefuroxime axetil and cefaclor; Tmax and t1/2 were relatively higher for ceftibuten, resulting in

a 3.5 times higher AUC than cefixime, cefuroxime axetil and cefaclor. Four oral

cephalosporins can be compared on basis of these pharmacokinetic data; however,

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comparative susceptibility data must also be under consideration. The mean clearances were

similar for the cefixime, cefuroxime axetil and cefaclor in the range of 20.4–27.0 L/hour;

ceftibuten had approximately 4-fold less clearance, 5.45 L/hour. The serum half-lives were

prolonged for ceftibuten (2.35 hr) and cefixime (2.38 hr) in comparison with cefuroxime

axetil (1.30 hr) and cefaclor (0.693 hr). So,these drugs differed in maximum concentration,

time to peak serum drug level, area under the time versus concentration curve and apparent

volume of distribution.

2.6 Cefixime and other drugs:

Drug–drug interactions are important issue today in health care. It is realized now that

alteration in the metabolic enzymes, present in liver and other extra-hepatic tissues can

explain many of these drug–drug interactions and most of hepatic cytochrome P450 (P450 or

CYP) enzymes are affected by previous administration of other drugs resulting in the major

pharmacokinetic interactions between drugs. In co-administration of drugs, some can act as

potent enzyme inhibitors whereas other drugs are enzyme inducers. But reports of enzyme

inhibition are much more common. For giving multiple-drug therapies appropriately it is very

important to understand the mechanisms of this enzyme inhibition or enzyme induction. In

future, it may help physicians for identification of the individuals who are at greatest risk for

drug interactions and adverse events (Tanaka, 2002).

2.6.1 Treatment of uncomplicated UTIs in women:

Cefixime and Ofloxacin:

Cefixime, a broad spectrum antibacterial agent, is effective against certain

uropathogens. Maximum concentrations of 3 to 4 µg/ml are achieved in serum after 3-4 hr of

a cefixime Tablet of 400 mg. Serum half-life (3-4 hr) is longer than other oral β-lactam

antibiotics. Additionally, after single dose of 400 mg orally, a concentration of cefixime in

urine for 90% of the most common urinary pathogens is above the MICs (Faulkner et al.,

1987b).

In woman uncomplicated cystitis is apparently treated by approximately three day

regimen of antibiotics. Cure rates of this regimen can be compared with that of the longer

therapy course, along with incidence of low adverse effects observed with the single dose of

therapy (Johnson and Stamm, 1989).

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Single-dose or short-course or 3-day regimen of quinolones and cotrimoxazole are as

efficacious as the other longer therapy courses (Hooton et al., 1991); however, comparable to

course of 3-day or single-dose, β-lactams were found more effective when administered for

five or more days (Norrby, 1990).

3-day regimen of ofloxacin (200 mg two times a day) and cefixime (400 mg once a

day) to treat UTIs in women (uncomplicated cystitis) were compared in a randomized double

blind study. Clinically cure rates for two groups of women were 81% and 84% after 4 weeks

and 89% and 92% after 7 days whereas microbiologically cure rates (free of bacteriuria) for

these two groups of women were 77% and 80% after 28 days and 83% and 86% after 7 days.

The three days ofloxacin regimen appeared to be as effective as the three day regimen of

cefixime for treatment of uncomplicated cystitis in women (Raz et al., 1994).

2.6.2 Treatment of uncomplicated gonorrhea in men:

Cefixime versus amoxicillin plus probenecid:

In a randomized study, a 3 g amoxicillin plus 1 g probenecid cured 44 of 46 men in

comparison with 96 cures of 97 in whom receiving a single 800 mg-cefixime for treatment of

uncomplicated gonococcal urethritis. Both of these regimens were not effective against

infection coexisting with Ureaplasma urealyticum and Chlamydia trachomatis. Cefixime was

tolerated well with mild and self limited adverse effects (David et al., 1990). Neisseria

gonorrhoeae has high susceptibility to cefixime In-vitro (Bowie et al., 1987). Cefixime had

interaction with probencid; therefore, its concomitant use with probencid should be avoided

(Jayatilaka and Kinghorn, 2006).

2.6.3 Effect of an (aluminum and magnesium containing) antacid on pharmacokinetics

of cefixime:

Aluminum and magnesium containing non systemic antacids are widely used for

treatment of disorders of gastrointestinal tract. When co-administered, antacids interfere with

absorption of many drugs, including cefuroxime axetil, fluoroquinolone and tetra-cycline

antibiotics (Sommers et al., 1984; Lode, 1988).

In an interaction study in dogs, antacids decreased significantly the bioavailability of

oral cefixime, however, no significant reduction in oral bioavailability of cefixime was noted

with co-administration of an aluminum-magnesium antacid (Healy et al., 1989).

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2.6.4 Enhancement in bioavailability of cefixime by nifedipine in human:

Absorption rate of cefixime was increased significantly by nifedipine. Cefixime has

absolute bioavailability of 31±6% when given alone while 53%±1% when present with

nifedipine. It is concluded that apparently an active process plays an important role in

absorption of cefixime in humans which may be modified by a CCB (calcium channel

blocker) i.e. nifedipine (Duverne et al., 1992). In rats, as similar to the amoxicillin,

absorption of cefixime from intestine occurs with help of an active transport mechanism

which involves a pH-dependent dipeptide transporter (Tsuji et al., 1987a,b).

2.6.5 Interaction between beta-blocker antihypertensive and β-lactam antibiotic:

Bioavailability of beta lactam antibiotic can be increased by using ca+2 channel

blocker. The study was conducted in human being. The result indicated that by using ca -

channel blocker there was an increase in intestinal epithelial cell uptake of cefixime (Wenzel

et al., 2002).

2.6.6 Carbamazepine:

Carbamazepine levels are elevated after concomitantly administration of cefixime.

Drug monitoring may help to detect the alteration in carbamazepine plasma-concentrations

(Baltimore, 2005).

2.6.7 Warfarin and anticoagulants:

The influence of cefixime was reported on liverenzymes (cytochrome P450).

Cefixime could interact with warfarin and increases its anticoagulant response (Lakshmi et

al., 2012). When cefixime is concomitantly administered, prothrombin time increases without

or with any clinical bleeding (Baltimore, 2005).

2.6.8 Cefixime bests ceftriaxone:

Both oral cefixime and intramuscular ceftriaxone do the trick against uncomplicated

Neisseria gonorrhoeae cervicitis in adolescents. But cefixime, which is the only one of the

single-dose antibiotics recommended for patients younger than 17, has several other

advantages as well: Although more expensive than ceftriaxone, cefixime is painless, simpler

to administer and minus the risk of needle stick (Lippincort and Wilkins, 1996).

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The treatment of quinolone unresponsive or resistant infection due to S. typhi is not

clear. A 3rd-generation parenteral cephalosporin, such as ceftriaxone, is a convenient choice.

An oral third generation cephalosporins, as cefixime, may be a reasonable option for less

seriously ill patients (Girgis et al., 1995a,b).

2.6.9 Drug / laboratory-test interactions:

In tests using nitroprusside, a false +ve reaction may result for the ketones in urine but

it was not with those using nitroferricyanide (Baltimore, 2005).

False +ve reaction may occur for glucose in the urine using Fehling's solution or

Benedict's solution, when cefixime is administered. Glucose tests which are based on the

enzymatic glucose oxidase reactions are recommended to be used (Baltimore, 2005).

During treatment with other cephalosporin antibiotics, a false +ve direct Coombs test

has been reported; so, a positive Coombs test may be due to the drug (Baltimore, 2005).

2.6.10 Food interactions:

Food affect the bioavailability of certain first, second and third generation

cephalosporin antibiotics such as cefaclor, ceftibuten etc. But the bioavailability of first

generation cephadroxil and cephalexin, cefprozil of second generation cephalosporins and

cefixime that belongs to third generation cephalosporin was not affected by the food (Levison

and Levison, 2009). A decrease in rate of absorption is observed when stomach is empty but

extent of absorption does not alter.

2.7 Determination of cefixime:

2.7.1 Estimation of cefixime in body fluids:

Many different assay procedures are reported in literature to estimate cefixime in

formulation, blood and urine etc. These include many different methods but the most

common used methods are:

Bioassay or Microbiological method or also called the disc diffusion method (Brittain,

1985; Nies, 1989; Eldalo et al., 2004).

Recently high-pressure liquid choromatography (HPLC) has found application in

determination of drugs in biological fluids or body fluids and several methods for analysis of

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antibiotics have been reported. Different HPLC procedures for quantification of cefixime in

serum and urine were developed (Guay et al., 1986; Westphal et al., 1993; Leroy et al., 1995;

Zendelovska et al., 2003; Asiri et al., 2005; Adam et al., 2012).

2.7.2 Different methods of analysis of cefixime:

Reviewing the literature revealed that several methods are developed to quantify the

cefixime in pure form, in pharmaceutical formulations / preparations or in biological samples,

whether as single active ingredient or in combination with any other drugs. These methods

include HPLC, high performance thin layer chromatography (HPTLC), spectrophotometric,

spectrofluorimetric, electrophoretic and voltammetric methods.

2.7.2.1 HPLC procedures for determination of the cefixime formulations:

British Pharmacopoeia (2011) stated HPLC methods for analysis of cefixime and

related substances on column C-18 (12.5 cm x 4 mm) at 40 °C temperature with

tetrabutylammonium hydroxide (pH adjustment to 6.5 with dilute phosphoric acid) and

acetonitrile (3:1) as a mobile phase with 1 ml/min of flow rate and UV detection at 254 nm.

United States pharmacopoeia (USP, 2007) recommended a similar HPLC method but

the reference standard and the sample were dissolved in pH 7 phosphate buffer.

Several methods of HPLC have been developed to determine cefixime in bulk and in

pharmaceutical dosage forms. All of these methods have used reversed phase C-18 columns

but with different dimensions (4 and 4.6 mm internal diameter, 10, 15 and 25 cm length).

Different mobile phases have been used (phosphate buffer with acetonitrile, phosphate buffer

with methanol, tetrabutylammonium hydroxide with acetonitrile, methanol with water and

acetonitrile with methanol with ammonium acetate). In these methods flow rates of 0.8, 1and

2 ml/min were used and detection was done by UV absorption at different wavelengths (254

nm, 285-287 nm and 295 nm) [Gonzalez-Hernandez et al., 2001; Shah and Pundarikakshudu,

2006; Arshad et al., 2009; Saikrishna et al., 2010; Raj et al., 2010; Pasha et al., 2010].

Several Reverse Phase HPLC methods were validated and developed with UV

detectors for simultaneous analysis of cefixime with other drugs in the same dosage form. For

example, a RP-HPLC procedure, using C-18 column, has been validated to simultaneously

determine cefixime and cloxacillin in Tablets. Mobile phase was prepared by mixing

phosphate buffer (of pH 5), acetonitrile and methanol and 2ml/min was the flow rate for

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mobile phase with U.V. detection at 225-nm. Method was observed linear in range of 160-

240 µg ml-1 and 400-600 µg ml-1 with retention times 5.6 and 6.2 min for cefixime and

cloxacillin, respectively. It was concluded that the method was rapid and sensitive

(Rathinavel et al., 2008).

Developmentand validation of a similar RPHPLC procedure for simultaneous

detection of cloxacillin and cefixime in Tablets was performed by using C-8 column, mobile

phase of acetonitrile and tetrabutylammonium hydroxide, flow rate with 1 ml/min alongwith

Ultra-Voilet detection at 225 nm. This method was found linear in range of 10-50 µg ml-1 and

25-125 µg ml-1 and retention time 5.75 and 11.9 min for cefixime and cloxacillin,

respectively (Wankhede et al., 2010).

For determination of combination of dicloxacillin and cefixime in Tablets, a RP-

HPLC method was developed and validated. C-18 column was used and mixture of

acetonitrile and potassium hydroxide buffer as mobile phase with ultraviolet detection at 220

nm and flow rate of 1 ml/min. Linearity obtained in the range of 60-140 µg.ml-1 (Kathiresan

et al., 2009).

In an RP-HPLC method to detect cefixime and ornidazole combination in the Tablet

dosage form, C-18 column was used and acetonitrile with 40 mM KH2PO4 as a mobile phase

and its flow rate was 1 ml/min at 310nm UV detection. Retention time of cefixime and

ornidazole were 2.75 min and 6.67 min, respectively (Sudhakar et al., 2010).

In another method of HPLC analysis of cefixime and ambroxol simultaneously by

using C-18 column and actonitrile with methanol was used as mobile phase. Ultravoilet

detector was used at 254 nm with 1.68 and 3.7 min retention time and linearity ranges from

4-18 and 4-28 µg/ml, respectively, for cefixime and ambroxol (Deshpande et al., 2010).

In development of a HPLC estimation of cefixime and cefuroxime axetil in bulk and

in dosage form by using column of C-18 with U.V. detection at 254 nm, a mixture of

methanol and water was used as mobile phase (Raj et al., 2010).

In description of a RP-HPLC method to determine cefixime and erdosteine

simultaneously in dosage forms, C-8 column was as stationary phase while mobile phase was

a combination of tetrabutyl ammonium hydroxide (having pH adjustment to 6.5) with

acetonitrile in a ratio of 2:1. Detection was done by UV at 254 nm, linearity obtained in the

171

range of 2-22 µg ml-1 for cefixime and 3-33 µg ml-1 for erdosteine, with retention time 10

min for cefixime and 5.4 min for erdosteine (Dhoka et al., 2010).

A RPHPLC method was used for the quantification of cefixime and potassium

clavulanate simultaneously in Tablet dosage forms. C-18 column was used as stationary

phase and mobile phase was composed of methanol and phosphate buffer and detection was

at 220nm. Result values were found in linear range of 20-100 µg ml-1 and 12.5-62.5 µg ml-1

and retention time 7.3 and 2.4 min for cefixime and potassium clavulanate, respectively

(Kumudhavalli et al., 2010).

Another RPHPLC method was described to simultaneously measure the cefixime and

potassium clavunate in Tablet forms, using a mixture of methanol and tetra butyl ammonium

hydroxide solution as mobile phase with 1 ml/min flow rate at 40ºC. The detection of

compound was done at 230 nm and 4.63 min and 11.89 min was the retention time for

potassium clavulanate and cefixime, respectively, and linearity was 10-180 µg ml-1 for

clavulanic acid and 10-360 µg ml-1 for cefixime (Basu et al., 2011).

According to a published RPHPLC procedure for the simultaneous estimation of

cefixime and ofloxacin in Tablets, C-8 neosphere was the column used and methanol with

potassium dihydrogen phosphate buffer was the mobile phase used. Detection was done at

290nm. Linearity was found in range of 1-10 µg ml-1 for both of these drugs (Khandagle et

al., 2011).

A similar method for separation and detection of cefixime and ofloxacin in Tablets

was developed with some differences in column and mobile phase used. The column used

was C-18 and mobile phase used was methanol and 25Mm phosphate-buffer (40:60 v/v) and

UV detection at 290 nm. Respective retention times for cefixime and ofloxacin were 2.5 and

7.8 min. The method was linear in range of 5-25 µg ml-1 for both drugs (Natesan et al., 2011).

Moreover, several RPHPLC methods were developed to estimate cefixime in the

biological fluids:

In a published RPHPLC method for determination of cefixime in serum of human, the

method was linear from 0.1 – 30 µg ml-1 for serum assay and from 5 – 100 µg ml-1 for the

urine assay (Falkowski et al., 1987).

172

In another developed RPHPLC method for analysis of five oral cephalosporins in

human serums, mobile phase was prepared by mixing methanol: monobasic phosphate buffer

(20:80), flow-rate 2 ml/min in C-8 column and ultraviolet detection was at 240 nm. The

authors concluded that this method has advantages over previous methods in that the same

conditions are used for five drugs and at clinically significant concentrations (McAteer et al.,

1987).

A published RP-High Pressure Liquid Chromatography method for analysis of

cefixime and cefotaxime simultaneously in the plasma, utilized a column of C-8 and mobile

phase of methanol and KH2PO4 (pH 2.2) (25:75, v/v). pH of buffer was adjusted to 2.2 (by

additionof small quantity of concentrated ortho-phosphoric acid). Detection was carried out

by UV and the method was found to be linear over the concentration range 0.2-12 µg ml-1 for

cefixime and 0.2-50 µg ml-1 for cefotaxime in samples of plasma (Zendelovska et al., 2003).

An HPLC analysis was developed to analyze cefixime in blood / plasma to compare

two pharmaceutical preparations (Pisarev et al., 2009).

A fast HPLC method was published for analysis of third generation three

cephalosporins including cefixime in human plasma. The method was performed by use of C-

18 column along with methanol and phosphate buffer as mobile phase having 1 ml/min flow

rate and UV detection at 230 nm. Three drugs were separated within 7 minutes (Ali et al.,

2011).

A LC-MS (liquid chromatographic tandem mass spectrometric) method was

developed for cefixime analysis in human serum/plasma. The method was performed on a C-

8 column coupled with a mass spectrometer. Water: acetonitrile: formic acid (60:40:0.5,

v/v/v) constituted the mobile phase. This method was linear in range of 0.05-8 µg per ml

(Meng et al., 2005).

Additionally, several HPTLC methods were developed for the simultaneous

determination of cefixime with other drugs in the same dosage form.

In a developed HPTLC-method to estimate cefixime, ceftriaxone and cefotaxime in

drug dosage forms, methanol- ethyl acetate-water-acetone were used as mobile-phase

(2.5:5:1.5:2.5 v/v/v/v) [Jovanovic et al., 1998].

173

An HPTLC procedure was developed and validated to estimate of cefixime and

ofloxacin in Tablets. Methanol-ethyl acetate-ammonia (3.5-3.5-1.5 v/v/v) were used as

mobile phase at 295nm UV detection. Results were linear in range of 50 to 500 ng/band for

both cefixime and ofloxacin (Khandagle et al., 2010).

A validated HPTLC technique described to analyze cefixime and erdosteine in bulk

form and in combined preparations has the mobile phase composing of ethyl acetate, acetone,

methanol and water (7.5: 2.5: 2.5: 1.5) and densitometric determination at 235 nm. The

method was performed on the plates of aluminium which were pre-coated with silica-gel

60F-254. The results were found linear in range of 100-500ng/band and 150-750 ng/band for

cefixime and erdosteine, respectively (Dhoka et al., 2013).

Another HPTLC-method development and validation, to detect ofloxacin and

cefixime simultaneously in Tablets used n-butanol: ammonia: water: DMSO (8:3:1:2,

v/v/v/v) as a mobile phase. This separation was performed on aluminum foil plates percolated

with silica gel 60GF-254. Densitometric detection was performed at 297 nm. Linearity was in

the range of 30-180 ng/spot for both drugs (Rao et al., 2011).

In another described HPTLC-method for simultaneous estimation of ambroxol-

hydrochloride and cefixime-trihydrate, the separation was done on aluminium sheets of the

silica-gel 60-F254 by using methanol: acetonitrile: triethylamine (1: 8.2: 0.8, v/v/v) as a

mobile phase. The method linear in range of 200 to 1000 ng/spot for cefixime and ambroxol,

with densitometric measurements of their spots at 254 nm (Deshpande et al., 2010).

In another published and validated HPTLC densitometric technique for analysis of

ornidazole and cefixime-trihydrate in bulk and in Tablets, the thin layer chromatography

(TLC) aluminium-sheets covered with silica-gel 60 F254 with n-butanol, methanol, toluene,

ammonia 5:2:1:5 (v / v / v / v) were used as a mobile phase. The results were found linear in

the range of 360-840 ng/band for cefixime and 900-2100 ng/band for ornidazole (Devika et

al., 2010).

A high-performance capillary electrophoretic method was also developed for

detection of cefixime and its metabolites (Honda et al., 1992).

An electrophoretic method to determine cefuroxime axetil and cefixime trihydrate in

pharmaceutical dosage forms and in bulk drug was described (Raj, 2010).

174

2.7.2.2 Spectroscopic Analysis of cefixime Formulations:

Different methods have been developed; including high performance liquid

chromatography, liquid chromatography mass spectrometry, voltammetry and capillary

electrophoresis for analysis of cefixime (Azmi et al., 2013).

Certain spectrophotometric methods have been developed to determine cefixime

Tablets using different hydrotropic agents as urea, sodium tartarate, sodium acetate, sodium

citrate and others and then cefixime was determined by conventional spectrophotometric

estimation at 288 nm or by area under curve method, these methods exhibit linearity range of

5-30 µg ml-1 (Maheshwari et al., 2010; Pareek et al., 2010). The role of different hydrotropic

agents in the determination of cefixime by HPTLC method was also studied (Pareek et al.,

2010).

In another study, two spectrophotometric methods were developed to estimate

cefixime and ornidazole simultaneously in Tablet dosage form. The first method is first order

derivative spectroscopy, wavelengths selected for quantification were 311.5 nm for cefixime

and 290 nm for ornidazole. Area under curve (AUC) method is the second method and AUC

in the range of 285-295 nm for cefixime and 307-317 nm for ornidazole were selected for the

analysis (Nanda et al., 2009a,b).

In another publication two methods of spectrophotometry stated for simultaneous

quantification of cefixime and ornidazole in Tablets, first method (Vierodt's method) is based

on simultaneous equations obtained by using mean absorptive values. For analysis selected

wavelengths were 290 nm (ʎmax of cefixime) and 312 nm (ʎmax of ornidazole), respectively, in

methanol. Q-analysis method is the second method which is based on absorbance ratio at two

selected wavelengths 303 nm (iso-absorptive point) and 312 nm (ʎmax of ornidazole) and the

concentration of each component is calculated from specific equations (Nanda et al.,

2009a,b).

Development of two spectrophotometric methods for assay of cefixime and ofloxacin

simultaneously from Tablets, first method involves formation of simultaneous equations at

234-nm (ʎmax of cefixime) and 296nm (ʎmax of ofloxacin). Second method involves formation

of absorbance ratio equation at 275nm (isoabsorptive point) and 296-nm (ʎmax of ofloxacin)

using methanol as a solvent (Dube et al., 2011).

175

A colorimetric procedure for simultaneous determination of cefixime and ofloxacin in

same formulation were developed. Ofloxacin developes a product of orange color in presence

of ferric chloride solution in acidic medium and absorbance of orange colored species formed

was measured at wavelength of 435 nm against reagent blank. Cefixime forms a product of

green color with Fehling-solution and the absorbance of this greenish species formed was

measured at 490-nm wavelength against reagent blank (Kumar et al., 2011).

In a validated spectrofluorimetric method published to analyze cefixime in

pharmaceuticals and in pure forms, the fluorescent product showed maximum fluorescence

intensity at ʎ 378 nm after excitation at ʎ 330 nm. The method was linear in range of 0.02-4

µg per ml (Shah et al., 2011).

A spectrofluorimetric method was studied for analysis of cefixime, cephalexin and

cefotaxime in pharmaceuticals. Method was based on the reaction between cefixime and 1, 2 -

NQS (naphthoquinone-4-sulfonic) at pH 12.0 to give highly fluorescent derivative extracted

with chloroform and then measured at 600 nm after excitation at 520 nm. The method was

linear in range of 10-35 ng ml-1 (Elbashir et al., 2011).

A newer spectrofluorimetry for determination of cefixime and other two

cephalosporins in pharmaceutical formulation was developed. The method based on reaction

between cefixime and HPTS (8-hydroxy-1,3,6-pyrenetrisulfonic acid trisodium salt) at pH

12.0 to give highly fluorescent derivative extracted with chloroform and then measured at

520 nm after excitation at 480nm (Ahmed et al., 2013).

Volummetric methods also have been developed to determine cefixime in dosage

forms and biological fluids (Reddy et al., 2003; Golcu et al., 2005; Jain et al., 2010).

176

CHAPTER III

MATERIALS AND METHODS

Pharmacokinetics and bioequivalence of two brands of cefixime were determined in healthy

adult female and male human subjects. The experimental protocol for the present study is given

below:

3.1 Experimental subject:

Twenty healthy adult human subjects, ten each of either sex, were selected for present study.

Description of experimental subjects has been presented in Table 3.1 and Table 3.2 and record

of their laboratory investigations i.e. blood group, complete blood composition (CBC),

Erythrocyte sedimentation rate (ESR), lipid profile, liver function test (LFT), blood urea and

creatinine, random blood sugar and screening for hepatitis-b and hepatitis-c have been shown in

appendices 1 and 2.

3.1.1 Selection criteria of volunteers:

177

Volunteers were randomly selected and experiments were performed at the Department of

Physiology and Pharmacology, University of Agriculture, Faisalabad. Selection of volunteers

was according to the following criteria:

Volunteers of age between 25 & 35 years were selected.

Weight of all volunteers was recorded.

Height of all volunteers was measured.

Blood pressure, pulse rate and temperature were recorded for all the subjects and were

found in its normal range.

No female volunteer was in period of her menstrual cycle.

Volunteers had no kind of disease or abnormality.

No subject had history or evidence of hepatic, cardiac, respiratory, neurological,

immunological, renal, gastrointestinal or hematological deviations or any acute or

chronic disease.

Clinical examination and necessary laboratory investigations (hematology and

biochemistry) were performed for each individual before selection.

Volunteers had not taken any other medication at least seven days before start of the

experiment.

Each experimental unit had no allergy to cefixime or other beta-lactam antibiotics.

Written consent was taken from each volunteer. All the selected volunteers were

informed about the objective of study, frequency of blood sampling and possible side

effects of the drug which they might face during the study period.

Sr. No. Age

(years)

Height

(meter)

Body weight

(Kg)

Temperature

(Fº)

Blood Pressure

(mmHg)

Systolic Diastolic

1 32 1.73 70 98.6 120 80

2 26 1.7 65 98.0 120 70

3 29 1.65 62 98.6 124 80

178

Table 3.1: Description of 10 healthy adult female volunteers involved during

investigations of pharmacokinetics and bioequivalence of cefixime.

4 28 1.6 60 98.4 110 70

5 25 1.58 58 98.4 120 74

6 27 1.59 59 98.6 120 80

7 30 1.66 64 98.2 118 70

8 31 1.62 61 98.0 120 80

9 33 1.56 56 98.6 110 70

10 29 1.61 60 98.4 120 60

Mean±SE 29±0.82 1.63±0.02 61.50±1.27 98.38±0.08 118.20±1.44 73.40±2.11

Sr. No. Age

(years)

Height

(meter)

Body

weight

(Kg)

Temperature

(Fº)

Blood Pressure

(mmHg)

Systolic Diastolic

1 25 1.82 72 98.6 120 70

2 27 1.9 79 98.6 110 76

3 29 1.78 68 98.4 100 70

4 26 1.8 74 98.6 110 80

5 31 1.75 73 98.0 120 70

6 33 1.73 70 98.2 120 80

179

Table 3.2: Description of 10 healthy adult male volunteers involved during investigations

of pharmacokinetics and bioequivalence of cefixime.

3.2 Medicines:

Two commonly prescribed brands of cefixime were used in present investigations,

one being multinational brand and most expensive in market and the other being national one

and was of the lowest cost.

3.2.1 Multinational brand of cefixime:

Cefspan® 400 mg capsule (Barrett Hodgson Pakistan (Pvt.) Ltd. F/423, Karachi-

75700, Pakistan) Batch number MC-460, Expiry date 06-14, Retail Price Rs.102.50 per

capsule.

3.2.2 National brand of cefixime:

Ceforal-3® 400 mg capsule (Zafa Pharmaceuticals Laboratories (Private) Ltd. L-1/B,

industrial area, Karachi-75950, Pakistan) Batch number 03, Expiry date 04-15, Retail Price

Rs. 32.00 per capsule.

7 27 1.7 67 98.6 120 80

8 29 1.89 81 98.8 110 70

9 28 1.77 75 98.0 100 70

10 30 1.76 71 98.6 120 80

Mean±SE 28.50±0.76 1.79±0.02 73.00±1.41 98.44±0.09 113.00±2.60 74.60±1.58

180

3.3 Experimental design:

Each of cefixime brands was administered orally in 10 healthy adult female and 10

healthy adult male subjects with a wash out period of 7 days between two administrations.

Volunteers might be ambulatory during the study but were prohibited from strenuous activity

on sampling days.

3.3.1 Sample collection:

In each experiment a blank blood sample was collected prior to drug administration. More

blood samples were taken with hourly interval up to 6 hours and then on 12 and 24 hours,

post medication. Samples were collected aseptically in heparinized centrifuge tubes from

forearm vein through IV cannula of 20G needle and then centrifuged at 3000 rpm for 5

minutes for plasma separation. The collected plasma was decanted in polypropylene tubes

and stored frozen at -20°C until assayed.

3.4 Analytical method:

The concentration of cefixime in plasma was measured with a sensitive, selective and

accurate High Performance Liquid Chromatographic (HPLC) method (Alshare, 1999).

3.4.1 Chemicals:

All the chemicals used were of analytical grade. Main chemicals used in HPLC

analysis of cefixime are listed in the following Table 3.3 with their sources.

Table 3.3: Chemicals used for analysis of cefixime by HPLC method.

Sr # Chemical Name Source

1 Cefixime-standard

(As cefixime trihydrate 99%)

Pharmagen Ltd., Lahore, Pakistan

2 Methanol Fisher Scientific Limited, UK

3 Acetonitrile Fisher Scientific Limited, UK

4 Monobasic sodium phosphate Merck Germany

5 Orthophosphoric acid Merck Germany

181

All the above mentioned chemicals were of analytical grade. Cefixime standard (as

cefixime trihydrate, 99%) was a kind gift from the Pharmagen Ltd., Lahore, Pakistan. All the

purchased solvents were HPLC grade. Acetonitrile and methanol were from Fisher Scientific

Limited, UK, and monobasic sodium phosphate and phosphoric acid were from Merck,

Germany.

3.4.2 Instrumentation and chromatographic conditions:

Chromatography was performed with a High Performance Liquid Chromatograph

(Sykam, S-1122) and drug was determined using UV/Visible detector (Sykam, S-3210). The

output of the detector was monitored with computer software (Peak Simple Chromatography

Data System, Buck Scientific Inc., East Norwalk). A stainless steel column packed with

YMC pack A-312 (Thermo Hypersil-Keystone, BDS-C18 with 250 x 4.6 mm dimensions and

5 µm particle size) was used. The column was protected with a pre-column (Guard-Pak™)

filled with a μBondapak™ C18 cartridge (Thermo Hypersil, England). Separation of cefixime

was achieved at 30ºC, using an isocratic mode. The UV detector was set at 275 nm and the

flow rate was 1 ml/min.

3.4.3 Preparation of mobile phase:

The mobile phase was prepared fresh on the day of analysis by combining 170 ml of

acetonitrile, 1.36g of monobasic sodium phosphate, 830 ml of distilled water, and 85%

phosphoric acid for the adjustment of pH up to approximately 2.7, and was filtered and

degassed by vacuum before use.

3.4.4 Cefixime standard solutions:

Stock solution of cefixime was prepared by dissolving 11.4 mg of the compound

(equivalent to l0 mg of cefixime, corrected for purity) in 1.0 ml of HPLC-grade methanol and

the mixture was diluted to 10 ml with distilled water. This stock solution, equivalent to 1.0

mg/ml, was refrigerated at 3°C for up to one week.

Then 1.0 mg/ml of the stock was further diluted 1:10 with distilled water to prepare an

additional standard that was l00 µg/ml.

3.4.5 Plasma calibration standard:

182

Calibration standard for the plasma assay was prepared by adding 100 µl of the 100

µg/ml cefixime stock solution to appropriate volume of drug-free plasma. Plasma cefixime

calibration standard curve was prepared at concentration of 1, 2, 3, 4 and 5 µg/ml.

Chromatograms of the standards of cefixime along with plasma blank are shown in Figs 3.1a-

3.1f and linearity curve has been shown in Fig 3.2. The calibration curve was constructed by

plotting the concentration versus peak area. The curves was linear over the range of 1 to 5 µg/ml

for cefixime (R2 = 0.9986; y = 43.1x+0.5) in human plasma.

3.4.6 Plasma sample preparation:

A 200 µl aliquot of the plasma standard or unknown sample was transferred to a

polypropylene 1.5-ml snap-cap centrifuge tube (Eppendorf, Hamburg, F.R.G) and 200 µ1 of

the methanol was added. The tube was vortexed at high speed for 30 seconds and centrifuged

at 15000 rpm for l0min. The clear supernatant was taken in a fresh disposable syringe and

filtered via syringe filter of 0.45 micron size filter medium.20 µl of the filtered sample was

injected into HPLC for each analysis.

Fig 3.1a: Chromatogram of blank plasma of healthy volunteer.

183

Fig 3.1b: Chromatogram of 1 µg/ml of cefixime standard.

Fig 3.1c: Chromatogram of 2 µg/ml of cefixime standard.

184

Fig 3.1d: Chromatogram of 3 µg/ml of cefixime standard.

Fig 3.1e: Chromatogram of 4 µg/ml of cefixime standard.

185

Fig 3.1f: Chromatogram of 5 µg/ml of cefixime standard.

186

Fig 3.2: Standard curve of cefixime.

3.4.7 Procedure:

Equal volume (20 µl) of the Standard Preparation and the Sample Preparation was

injected separately into the chromatograph. Chromatogram was recorded, and the area for the

major peaks for both was measured.

3.4.8 Quantitation:

Drug concentration in the unknown plasma sample was calculated by interpolation

from the linear least-squares regression line of the multi-level standard curve plot of peak-

height ratio versus cefixime concentration in the calibration standard curve.

3.5 Calculations:

y = 43.222x + 0.051R² = 0.9996

A

r

e

a

Concentration(lm/gµ)

187

Concentration of cefixime versus time data were used for calculating parameters of

pharmacokinetic and bioavailability.

3.5.1 Pharmacokinetic:

Pharmacokinetic calculations were done after one compartment open model with the

computer programme MW/PHARM version 3.02 by F. Rombout, in cooperation with

University Centre for Pharmacy, Department of Pharmacology and Therapeutics, University of

Gronigen & Medi/Ware, copy right 1987-1991. The definitions and/or formulae of kinetic

parameters derived are given in Table 3.4.

Table 3.4: Definitions and/or formulae of kinetic parameters derived.

Kinetics

parameters Units Definitions and/or method of calculation

B µg/ml Extrapolated zero time drug concentration of elimination phase.

Β hr-1 Overall elimination rate constant.

t1/2β hr Biological half life = 0.693/β

Vd l/kg Apparent volume of drug distribution. Vd = Dose/B

ClB l/hr/kg Total body clearance = Vd. β

3.5.2 Bioavailability:

Parameters of bioavailability were calculated by using method as followed by Gibaldi,

(1984).The definitions and/or formulae of bioavailability parameters derived are given in Table

3.5.

Table 3.5: Definitions and/or formulae of bioavailability parameters derived.

188

Kinetics

parameters Units Definitions and/or method of calculation

Cmax µg/ml It is the maximum concentration given by a drug in the plasma.

Tmax hr It is the time at which maximum concentration of drug is obtained in

the plasma.

AUC µg.hr/ml

It is the area under the plasma drug concentration versus time

curve, calculated by trapezoidal rule.

AUC = C.dt

(Where C is the plasma drug concentration at time t)

AUMC µg.hr2/ml

The first moment of a plasma drug concentration time profile is

the area under the curve resulting from plot of the product of time

and drug concentration versus time curve.

AUMC = C.t dt

( Where dt is the time interval and C.t is the product of plasma

drug concentration and time)

MRT hr

Mean residence time is the time required to eliminate 63.2% of the

dose from the body and is determined by the ratio of AUMC and

AUC.

(MRT = AUMC / AUC)

3.5.3 Bioequivalence:

Relative bioavailability of cefixime brands was calculated using method as followed

by Aboulenein et al. (2005). Estimates of extent and rate of absorption comparison in terms

of AUC and Cmax between the test (ceforal-3) and reference (cefspan) brands, respectively,

were calculated to evaluate either the brands are bioequivalent or not. The brands were

considered bioequivalent if the relative bioavailability for rate (Cmax) and extent (AUC) of

absorption were within the predetermined bioequivalence range of 80% to 125%.

189

3.6 Statistical Analysis:

Mean±SE for each concentration and parameter was calculated. Concentration of

cefixime versus time data were used for calculating parameters of pharmacokinetic and

bioavailability. Parameters of bioavailability were calculated by using method as followed by

Gibaldi, (1984). For bioequivalence study, ratio of AUC and Cmax between test and reference

brands was determined. Data was statistically analyzed by applying student’s paired t-test for

significance (P ≤ 0.05). Where necessary, comparison amongst parameters was carried out by

applying DMR conditional to the significance of ANOVA. Statistical analysis was carried out

with PC-program MStat-C by Freed, R.D. and Eisensmith. S.P., Michigan State University,

USA, and the figures were prepared using Microsoft Excel version 2003.

190

CHAPTER IV

RESULTS

Pharmacokinetics and bioequivalence of two brands of cefixime were investigated following a single oral

dose of 400 mg in healthy adult female and male volunteers. The results of plasma concentrations,

pharmacokinetic and bioavailability parameters for brands, cefspan and ceforal-3, of cefixime in female

and male groups are presented below:

4.1 Plasma concentration:

To determine the concentration of cefixime in the plasma, blood samples were taken from 10

healthy female and 10 male volunteers. Each volunteer was orally administered two brands of 400mg

cefixime capsule with a washout period of 7 days and the results are presented in Tables 4.1.1, 4.1.2, 4.1.4

and 4.1.5.

The concentration of cefspan and ceforal-3 at different time intervals after oral administration in

individual groups of female and male volunteers has been presented in Table and Fig 4.1.1 for cefspan in

females, Table and Fig 4.1.2 for cefspan in males, Table and Fig 4.1.4 for ceforal-3 in females and Table

and Fig 4.1.5 for ceforal-3 in males. Gender differences (Table and Fig 4.1.3, Table and Fig 4.1.6) and

brand differences (Table and Fig 4.1.7, Table and Fig 4.1.8) in plasma concentrations have been

compared by t-test and these results are also shown in their respective Tables. The statistical comparison

of mean±SE values of these concentrations amongst brands in male and male genders was carried out

with DMR test when ANOVA was significant (Table and Fig 4.1.9).

4.1.1 Plasma concentrations of cefspan

4.1.1.1 Female subjects:

From Table 4.1.1 it has been found that the mean±SE plasma concentration of orally

administered cefspan reached its maximum from 0.78±0.15 µg/ml at 1 hr to3.03±0.45 at 3hr and then

declined in a progressive fashion with passage of time to 0.19±0.04µg/ml at 24 hr. The mean±SE values

for cefspan concentration in plasma of10 healthy adult females have been plotted against time in Fig

4.1.1. Plasma concentration trend shows that it reached to maximum in 3 hours after drug administration

and declined progressively with passage of time.

4.1.1.2 Male subjects:

191

The values for the plasma concentration of cefspan in 10 healthy adult male subjects have been

shown in Table 4.1.2. The mean±SE concentration was 1.26±0.12 µg/ml at 1 hr after oral dose of cefspan

which reached maximum to 4.05±0.42 µg/ml at 4 hr and declined over time to 0.33±0.05 µg/ml at 24 hr.

The means±SE values for plasma concentration of cefspan in 10 males have been plotted in Fig 4.1.2

against time after oral dose. Like previous group, after maximum absorption plasma concentration

declined slowly.

4.1.1.3 Gender variation:

A statistical appraisal of gender differences in mean±SE plasma concentrations of cefspan in

females and males has been shown in Table 4.1.3 and Fig 4.1.3 indicating significant (P < 0.05) gender

differences only at 1 and 5 hours after drug administration.

192

Table 4.1.1: Mean±SE plasma concentrations (µg/ml) of cefspan following a single oral administration 400 mg in 10 healthy adult female subjects.

Subject

No.

Time after administration (hours)

1 2 3 4 5 6 12 24

1 0.77 3.05 5.12 3.71 2.58 2.46 1.27 0.21

2 1.99 2.02 4.06 3.19 3.08 1.57 1.08 0.38

3 0.42 1.55 2.11 2.32 2.09 1.03 0.47 0.15

4 0.54 0.92 2.18 2.23 1.46 1.34 0.49 0.28

5 0.56 2.75 3.99 4.53 2.25 1.59 0.87 0.01

6 0.82 0.92 1.17 3.24 1.62 2.21 0.70 0.19

7 0.33 0.94 4.41 1.71 1.81 1.76 0.82 0.26

8 0.77 1.06 1.22 2.14 2.51 2.09 0.99 0.07

9 1.10 2.23 3.97 2.93 2.32 2.30 1.95 0.01

10 0.47 1.53 2.07 3.73 2.49 1.62 1.38 0.31

Mean±SE 0.78±0.15 1.69±0.25 3.03±0.45 2.97±0.28 2.22±0.15 1.79±0.14 1.00±0.14 0.19±0.04

193

194

Fig 4.1.1: Mean±SE plasma concentrations (µg/ml) of cefspan on a semi logarithmic scale versus time following a single oral administration 400 mg in

10 healthy adult female subjects.

0.1

1

10

0 4 8 12 16 20 24

Co

nc

en

trati

on

(μ

g/m

l)

Time (hours)

195

Table 4.1.2: Mean±SE plasma concentrations (µg/ml) of cefspan following a single oral administration 400 mg in 10 healthy adult male subjects.

Subject

No.


1 2 3 4 5 6 12 24

1 1.27 1.74 2.09 2.75 2.14 1.97 1.19 0.39

2 1.69 1.76 3.45 5.21 4.74 2.49 1.71 0.33

3 1.64 3.29 4.34 4.58 5.82 6.62 1.13 0.42

4 1.57 1.69 2.44 2.69 2.91 2.72 1.53 0.56

5 1.19 2.35 3.43 3.12 2.04 1.99 1.10 0.21

6 0.82 2.02 3.31 6.10 5.56 2.04 1.64 0.39

7 0.87 1.13 2.82 2.77 1.97 1.55 0.82 0.07

8 1.78 2.04 6.15 3.36 3.09 2.18 1.46 0.38

9 0.91 1.41 2.18 4.04 2.09 1.43 0.73 0.45

10 0.87 2.77 3.24 5.89 6.83 4.04 0.63 0.07

Mean±SE 1.26±0.12 2.02±0.20 3.35±0.38 4.05±0.42 3.72±0.58 2.70±0.49 1.19±0.12 0.33±0.05

196

197


10 healthy adult male subjects.

0.1

1

10

0 4 8 12 16 20 24

Co

nc

en

trati

on

(μ

g/m

l)

Time (hours)

198

Table 4.1.3: Mean±SE plasma concentrations (µg/ml) of cefspan following a single oral

administration 400 mg in healthy adult female and male subjects.

*: Significantly (P < 0.05) different from the respective value.

NS: Non-significantly (P > 0.05) different from the respective value.

Time (hours) Female Male

1 0.78±0.15* 1.26±0.12

2 1.69±0.25 NS 2.02±0.20

3 3.03±0.45 NS 3.35±0.38

4 2.97±0.28 NS 4.05±0.42

5 2.22±0.15* 3.72±0.58

6 1.79±0.14 NS 2.70±0.49

12 1.00±0.45 NS 1.19±0.12

24 0.19±0.04 NS 0.33±0.05

199


healthy adult female and male subjects.

0.1

1

10

0 4 8 12 16 20 24

Co

nc

en

trati

on

(μ

g/m

l)

Time (hours)

Female Male

200

Table 4.1.4: Mean±SE plasma concentrations (µg/ml) of ceforal-3 following a single oral administration 400 mg in 10 healthy adult female subjects.

Subject

No.


1 2 3 4 5 6 12 24

1 0.35 0.56 1.85 3.45 4.58 2.86 0.68 0.03

2 0.68 2.37 3.00 3.83 2.69 1.88 0.77 0.07

3 1.22 1.36 1.81 2.81 2.23 2.09 0.89 0.01

4 0.56 1.85 2.82 1.99 1.85 1.06 0.63 0.08

5 1.34 2.04 3.33 5.12 2.07 1.71 0.94 0.05

6 0.59 1.69 4.62 2.30 2.21 1.41 0.56 0.03

7 0.42 1.43 2.63 3.64 2.69 1.97 0.89 0.12

8 0.63 1.55 1.64 2.30 1.48 1.31 0.68 0.19

9 0.42 0.66 2.14 2.98 2.69 1.74 0.56 0.23

10 0.61 0.79 1.38 2.28 2.39 2.82 0.68 0.33

201

Mean±SE 0.68±0.11 1.43±0.19 2.52±0.31 3.07±0.30 2.49±0.26 1.89±0.19 0.73±0.04 0.11±0.03

202

Fig 4.1.4: Mean±SE plasma concentrations (µg/ml) of ceforal-3 on a semi logarithmic scale versus time following a single oral administration 400 mg

in 10 healthy adult female subjects.

0.1

1

10

0 4 8 12 16 20 24

Co

nc

en

trati

on

(μ

g/m

l)

Time (hours)

203

Table 4.1.5: Mean±SE plasma concentrations (µg/ml) of ceforal-3 following a single oral administration 400 mg in 10 healthy adult male subjects.

Subject

No.


1 2 3 4 5 6 12 24

1 0.89 2.30 2.72 2.35 1.67 1.59 0.94 0.42

2 0.66 1.31 3.70 3.97 3.49 2.23 0.94 0.21

3 0.61 1.03 3.26 2.58 2.28 2.11 0.59 0.11

4 0.63 1.97 3.00 2.86 1.55 1.50 1.01 0.42

5 0.89 2.30 3.17 6.90 6.36 5.52 2.42 0.45

6 0.63 1.53 1.74 1.53 1.29 0.85 0.33 0.04

7 1.01 2.68 2.89 1.53 1.48 1.27 0.87 0.38

8 1.08 1.57 2.28 3.89 2.42 2.18 1.50 0.03

9 1.17 2.07 2.21 3.22 2.42 1.90 1.36 0.24

10 1.74 2.79 3.92 5.89 6.40 3.71 2.39 0.56

204

Mean±SE 0.93±0.11 1.96±0.18 2.89±0.21 3.47±0.56 2.94±0.61 2.29±0.43 1.24±0.22 0.28±0.06

205

0.1

1

10

0 4 8 12 16 20 24

Co

nc

en

trati

on

(μ

g/m

l)

Time (hours)

206


in 10 healthy adult male subjects.

207

Table 4.1.6: Mean±SE plasma concentrations (µg/ml) of ceforal-3 following a single oral





1 0.68±0.11 NS 0.93±0.11

2 1.43±0.19 NS 1.96±0.18

3 2.52±0.31 NS 2.89±0.21

4 3.07±0.30 NS 3.47±0.56

5 2.49±0.26 NS 2.94±0.61

6 1.89±0.19 NS 2.29±0.43

12 0.73±0.04* 1.24±0.22

24 0.11±0.03* 0.28±0.06

208

209


in healthy adult female and male subjects.

0.1

1

10

0 4 8 12 16 20 24

Co

nc

en

trati

on

(μ

g/m

l)

Time (hours)

Female Male

210

Table 4.1.7: Mean±SE plasma concentrations (µg/ml) of cefspan and ceforal-3 following a single

oral administration 400 mg in healthy adult female subjects.


Time (hours) Cefspan Ceforal-3

1 0.78±0.15 NS 0.68±0.11

2 1.69±0.25 NS 1.43±0.19

3 3.03±0.45 NS 2.52±0.31

4 2.97±0.28 NS 3.07±0.30

5 2.22±0.15 NS 2.49±0.26

6 1.79±0.14 NS 1.89±0.19

12 1.00±0.14 NS 0.73±0.04

24 0.19±0.04 NS 0.11±0.03

211

Fig 4.1.7: Mean±SE plasma concentrations (µg/ml) of cefspan and ceforal-3 on a semi logarithmic scale versus time following a single oral

administration 400 mg in healthy adult female subjects.

0.1

1

10

0 4 8 12 16 20 24

Co

nc

en

trati

on

(μ

g/m

l)

Time (hours)

Cefspan Ceforal-3

212


oral administration 400 mg in healthy adult male subjects.


Time (hours) Cefspan Ceforal-3

1 1.26±0.12 NS 0.93±0.11

2 2.02±0.20 NS 1.96±0.18

3 3.35±0.38 NS 2.89±0.21

4 4.05±0.42 NS 3.47±0.56

5 3.72±0.58 NS 2.94±0.61

6 2.70±0.49 NS 2.29±0.43

12 1.19±0.12 NS 1.24±0.22

24 0.33±0.05 NS 0.28±0.06

213

214


administration 400 mg in healthy adult male subjects.

0.1

1

10

0 4 8 12 16 20 24

Co

nc

en

trati

on

(μ

g/m

l)

Time (hours)

Cefspan Ceforal-3

215


oral administration 400 mg in healthy adult female and male subjects.

Mean values followed by different letters in a row indicate statistically significant (P < 0.05)

difference.


Cefspan Ceforal-3 Cefspan Ceforal-3

1 0.78±0.15 B 0.68±0.11 B 1.26±0.12 A 0.93±0.11 AB

2 1.69±0.25 A 1.43±0.19 A 2.02±0.20 A 1.96±0.18 A

3 3.03±0.45 A 2.52±0.31 A 3.35±0.38 A 2.89±0.21 A

4 2.97±0.28 A 3.07±0.30 A 4.05±0.42 A 3.47±0.56 A

5 2.22±0.15 B 2.49±0.26 AB 3.72±0.58 A 2.94±0.61 AB

6 1.79±0.14 A 1.89±0.19 A 2.70±0.49 A 2.29±0.43 A

12 1.00±0.14 AB 0.73±0.04 B 1.19±0.12 A 1.24±0.22 A

24 0.19±0.04 AB 0.11±0.03 B 0.33±0.05 A 0.28±0.06 A

216

217



0.1

1

10

0 4 8 12 16 20 24

Co

nc

en

trati

on

(μ

g/m

l)

Time (hours)

Female (Cefspan)

Female (Ceforal-3)

Male (Cefspan)

Male (Ceforal-3)

218

4.1.2 Plasma concentrations of ceforal-3:


The plasma concentration values of ceforal-3 given orally in 10 healthy adult female subjects

have been shown in Table 4.1.4 and presented graphically on a scale against time in Fig 4.1.4. The

mean±SE concentration of ceforal-3 was 0.68±0.11 µg/ml at 1hrwhich reached maximum to 3.07±0.30

µg/ml at 4 hr and then declined to 0.11±0.03 µg/ml at 24 hr after oral administration. After reaching its

maximum, the plasma concentration started to fall slowly until the last sample.


The plasma concentrations ofceforal-3 after oral administration in 10 healthy adult males has

been shown in Table 4.1.5. The mean±SE concentration of ceforal-3 at 1hr after oral dose was

0.93±0.11µg/ml reaching its maximum to 3.47±0.56 µg/ml at 4 hr and then decreased to 0.28±0.06 µg/ml

at 24 hours after dose given orally. The mean±SE values for plasma concentration of ceforal-3 after oral

administration in 10males have been plotted on a semi-logarithmic scale against time in Fig 4.1.5. The

plasma concentration revealed a monophasic progressive decline.


Gender differences in the mean±SE plasma concentrations of ceforal-3 in both gender groups are

shown in Table 4.1.6 indicating gender differences (P < 0.05) at 12 and 24 hrs, post medication.

4.1.3. Plasma concentrations of cefspan and ceforal-3:

4.1.3.1 Brand variation in female subjects:

A statistical appraisal of brand differences in mean±SE plasma concentrations of cefspan and

ceforal-3 in females has been shown in Table 4.1.7 and Fig 4.1.7. No significant (P < 0.05) difference

between both brands was observed when administered in females.

4.1.3.2 Brand variation in male subjects:

Brand differences in mean±SE plasma concentrations of cefspan and ceforal-3 in males are

shown in Table 4.1.8 and Fig 4.1.8. Both brands showed non significant (P ˃0.05) difference at any time

after dosing in males.

4.1.3.3 Brand variation in female and male Genders:

A further comparison of the mean±SE values for plasma concentrations of both brands, cefspan

and ceforal-3 in male and female genders, presented in Table 4.1.9 and Fig 4.1.9,showed that cefspan in

219

males had highest, cefspan in females andceforal-3 in males intermediate and ceforal-3 in females

showed lower plasma concentrations at most of the times after oral administration.

4.2 Pharmacokinetics:

Pharmacokinetics of two brands, cefspan and ceforal-3, of cefixime was determined in healthy

adult female and male subjects following oral administration of a single dose of 400 mg capsule.

Pharmacokinetic analysis was carried out by one compartment open model.

The results showing pharmacokinetic parameters (B, β, t1/2β, Vd and ClB) of cefspan and ceforal-3

administered in healthy adult female and male groups are given in Tables 4.2.1, 4.2.2, 4.2.4 and 4.2.5,

respectively. Comparison of mean±SE results of various pharmacokinetic parameters in 10 females and

10 males of each group are shown in Table 4.2.3 and Table 4.2.6, while, cefspan has been compared with

ceforal-3 in Table 4.2.7 and Table 4.2.8, respectively, with help of t-test. The statistical comparison of

mean±SE values of pharmacokinetic parameters of cefspan and ceforal-3 in females and males was

carried out by computing ANOVA and then applying DMR test (Table 4.2.9).

4.2.1 Pharmacokinetics of cefspan:


Mean±SE results of various parameters for pharmacokinetic of cefspan in 10 healthy adult

female subjects are shown in Table 4.2.1. It can be seen from the Table 4.2.1 that mean±SE values of

pharmacokinetic parameters; extrapolated zero time concentration (B) 5.14±0.74 µg/ml, elimination

rate constant (β) 0.21±0.03 hr-1, elimination half life (t1/2β) 3.99±0.54 hr, volume of distribution (Vd)

1.38±0.22 l/kg and total body clearance (ClB) 0.27±0.02 l/hr/kg, respectively, have been determined in

10 healthy adult female subjects following administration of cefspan 400 mg.


The mean±SE values for the pharmacokinetic parameters of cefspan in males are presented in

Table 4.2.2. The mean±SE values of pharmacokinetic parameters for B, β and t1/2ß in males were

5.94±0.78 µg/ml, 0.16±0.02hrs-1and 5.01±0.61 hours, respectively. Mean±SE value for Vd was 1.09±0.15

l/kg and that of ClB was 0.16±0.02 l/hr/kg.


Gender difference between pharmacokinetic parameters (mean±SE) of cefspan has been shown

in Table 4.2.3. Results showed that all the pharmacokinetic parameters of both genders were non-

significantly (P > 0.05) different except that of total body clearance (P < 0.05).

220

Table 4.2.1: Mean±SE pharmacokinetic parameters of cefspan following a single oral

administration 400 mg in 10 healthy adult female subjects.

Subject No. B β t1/2β Vd ClB

(µg/ml) (hr-1) (hr) (l/kg) (l/hr/kg)

1 7.16 0.20 3.52 0.80 0.16

2 3.38 0.11 6.62 0.62 0.17

3 2.74 0.15 4.78 2.35 0.34

4 2.22 0.10 6.69 2.69 0.28

5 7.36 0.36 1.94 0.94 0.33

6 3.67 0.16 4.34 1.85 0.29

7 4.68 0.18 3.76 1.34 0.26

8 4.84 0.24 2.88 1.36 0.33

9 9.59 0.44 1.59 0.73 0.32

10 5.77 0.18 3.83 1.16 0.21

Mean±SE 5.14±0.74 0.21±0.03 3.99±0.54 1.38±0.22 0.27±0.02

221

Table 4.2.2: Mean±SE pharmacokinetic parameters of cefspan following a single oral

administration 400 mg in 10 healthy adult male subjects.



1 3.31 0.10 7.02 1.68 0.17

2 7.89 0.17 3.99 0.64 0.11

3 8.25 0.15 4.54 0.71 0.11

4 4.02 0.09 7.49 1.34 0.12

5 4.35 0.14 4.87 1.26 0.18

6 8.85 0.19 3.56 0.65 0.13

7 5.41 0.25 2.73 1.23 0.31

8 4.94 0.12 5.86 1.00 0.12

9 2.82 0.09 7.66 1.89 0.17

10 9.59 0.29 2.43 0.59 0.17

222

Mean±SE 5.94±0.78 0.16±0.02 5.01±0.61 1.09±0.15 0.16±0.02

223

Table 4.2.3: Mean±SE pharmacokinetic parameters of cefspan following a single oral administration 400 mg in healthy adult female and male subjects.

Parameters Units Female

Male

B

µg/ml 5.14±0.74 NS 5.94±0.78

β

hr-1 0.21±0.03 NS 0.16±0.02

t1/2β

hr 3.99±0.54 NS 5.01±0.61

Vd

l/kg 1.38±0.22 NS 1.10±0.15

ClB

l/hr/kg 0.27±0.02* 0.16±0.02



224

Table 4.2.4: Mean±SE pharmacokinetic parameters of ceforal-3 following a single oral

administration 400 mg in 10 healthy adult female subjects.



1 4.83 0.27 2.54 1.18 0.32

2 8.50 0.46 1.51 0.72 0.33

3 6.33 0.35 1.99 1.02 0.35

4 3.63 0.19 3.59 1.84 0.35

5 7.54 0.29 2.41 0.78 0.22

6 5.62 0.29 2.34 1.21 0.36

7 5.56 0.23 3.06 1.12 0.25

8 2.66 0.13 5.46 2.47 0.31

9 4.46 0.19 3.62 1.57 0.30

10 4.00 0.15 4.69 1.67 0.25

Mean±SE 5.31±0.57 0.25±0.03 3.12±0.39 1.36±0.17 0.31±0.02

225

Table 4.2.5: Mean±SE pharmacokinetic parameters of ceforal-3 following a single oral

administration 400 mg in 10 healthy adult male subjects.



1 2.77 0.09 7.21 2.01 0.18

2 6.74 0.21 3.24 0.75 0.16

3 5.21 0.23 2.96 1.32 0.31

4 2.97 0.09 7.37 1.82 0.17

5 11.21 0.19 3.63 0.49 0.09

6 4.06 0.37 1.87 1.41 0.52

7 2.36 0.08 8.36 2.54 0.21

8 6.97 0.29 2.37 0.71 0.21

9 4.76 0.15 4.67 1.12 0.17

10 7.46 0.13 5.51 0.76 0.10

Mean±SE 5.45±0.86 0.18±0.03 4.72±0.72 1.29±0.21 0.21±0.04

226

227

Table 4.2.6: Mean±SE pharmacokinetic parameters of ceforal-3 following a single oral administration 400 mg in healthy adult female and male subjects.

Parameters Units Female

Male

B

µg/ml 5.31±0.57 NS 5.45±0.86

β

hr-1 0.25±0.03 NS 0.18±0.03

t1/2β

hr 3.12±0.39 NS 4.72±0.72

Vd

l/kg 1.36±0.17 NS 1.29±0.21

ClB

l/hr/kg 0.31±0.02* 0.21±0.04



228

Table 4.2.7: Mean±SE pharmacokinetic parameters of cefspan and ceforal-3 following a single oral administration 400 mg in healthy adult female

subjects.

Parameters Units Cefspan

Ceforal-3

B

µg/ml 5.14±0.74 NS 5.31±0.57

β

hr-1 0.21±0.03 NS 0.25±0.03

t1/2β

hr 3.99±0.54 NS 3.12±0.39

229

Vd

l/kg 1.38±0.22 NS 1.36±0.17

ClB

l/hr/kg 0.27±0.02 NS 0.31±0.02


Table 4.2.8: Mean±SE pharmacokinetic parameters of cefspan and ceforal-3 following a single oral administration 400 mg in healthy adult male subjects.


Ceforal-3

B

5.94±0.78 NS 5.45±0.86

230

µg/ml

β

hr-1 0.16±0.02 NS 0.18±0.03

t1/2β

hr 5.01±0.61 NS 4.72±0.72

Vd

l/kg 1.10±0.15 NS 1.29±0.21

ClB

l/hr/kg 0.16±0.02 NS 0.21±0.04


231

Table 4.2.9: Mean±SE pharmacokinetic parameters of cefspan and ceforal-3 following a single oral administration 400 mg in healthy adult female and

male subjects.

Parameters

Units

Female Male


B

µg/ml 5.14±0.74 A 5.31±0.57 A 5.94±0.78 A 5.45±0.86 A

β

hr-1 0.21±0.03 AB 0.25±0.03 A 0.16±0.02 B 0.18±0.03 AB

t1/2β

hr 3.99±0.54 AB 3.12±0.39 B 5.01±0.61 A 4.72±0.72 AB

Vd

l/kg 1.38±0.22 A 1.36±0.17 A 1.10±0.15 A 1.29±0.21 A

232

ClB

l/hr/kg 0.27±0.02 AB 0.31±0.02 A 0.16±0.02 C 0.21±0.04 BC

Mean values followed by different letters in a row indicate statistically significant (P < 0.05) difference.

161

4.2.2 Pharmacokinetics of ceforal-3:


The values for pharmacokinetic parameters (mean±SE) of ceforal-3 in 10females are presented in

Table 4.2.4. The mean±SE value of extrapolated zero hour drug concentration (B) observed in females

was 5.31±0.57 µg/ml and that of β was 0.88±0.09 hours-1. The t1/2ß, mean±SE value, was3.12±0.39 hr.

The mean±SE values for Vd and ClBwere1.36±0.17 l/kg and0.31±0.02 l/hr/kg, respectively.


Pharmacokinetic parameters (mean±SE) of ceforal-3 in males are shown in Table 4.2.5.

Mean±SE values of the B, β, t1/2ß, Vd and ClB were 5.45±0.86 µg/ml, 0.18±0.03 hours-1, 4.72±0.72hr,

1.29±0.21 l/kg and0.21±0.04 l/hr/kg, respectively.


Gender variation for pharmacokinetics values (mean±SE) of ceforal-3 administered in healthy

female and male subjects has been presented in Table 4.2.6. Total body clearance was significantly (P <

0.05) higher in females than in males while, all the remaining pharmacokinetic parameters remained non-

significantly (P > 0.05) different.

4.2.3 Pharmacokinetics of cefspan and ceforal-3:


Brand difference amongst pharmacokinetic parameters (mean±SE values) in females has been

shown in Table 4.2.7. Data showed non-significant (P > 0.05) results for all the pharmacokinetic

parameters of cefspan and ceforal-3 administered in female volunteers.


Table 4.2.8 represents the brand variation for pharmacokinetic parameters of cefspan and ceforal-

3 in males. All the pharmacokinetic values were non-significantly (P > 0.05) different for cefspan and

ceforal-3 given in healthy males.

4.2.3.3 Gender variation of cefspan and ceforal-3:

Table 4.2.9 showed that the mean±SE values of B were statistically similar (P > 0.05) for both

brands administered in females and males. Non significant (P > 0.05) gender variations were noted in the

mean values of elimination rate (ß) except that of cefspan in males and ceforal-3 in females (P < 0.05).

However, lowest mean value of ß was seen for cefspan in males (0.16±0.02 hr-1), intermediate for ceforal-

3 in males and cefspan in males (0.18±0.03 hr-1 and 0.21±0.03 hr-1) and highest for ceforal-3 in females

162

(0.25±0.03 hr-1). Similar statistical appraisal was noted for half life values of cefspan and ceforal-3 in both

genders. The mean±SE value of half life for cefspan in males (3.99±0.54 hours) and ceforal-3 in females

(4.72±0.72 hours) were significantly (P < 0.05) different. Nevertheless, the longest half life was recorded

for cefspan in males (5.01±0.61 hours) and shortest for ceforal-3 in females (3.12±0.39 hours).The mean

value of Vd for cefspan and ceforal-3 in females and males was found non significantly (P > 0.05)

different. Statistical significant (P < 0.05) gender variation was recorded in the mean±SE values of ClB for

cefspan and ceforal-3 in males and females, respectively, and also between ceforal-3 in females and

males. The highest mean value of ClB was seen for ceforal-3 in females (0.31±0.02 l/hr/kg), intermediate

for ceforal-3 in males and for cefspan in females (0.21±0.04 l/hr/kg and 0.27±0.02 l/hr/kg) and that of the

lowest one for cefspan in males (0.16±0.02 l/hr/kg).

4.3 Bioavailability

In present study, blood samples from 10 females and 10 males were collected after administration

of cefspan and ceforal-3 to each group followed by a wash out period of 7 days. Bioavailability

parameters (Cmax, Tmax, AUC, AUMC and MRT) were calculated for each brand in each group of gender.

The results of bioavailability of each brand in each group of gender have been shown separately

in Tables 4.3.1, 4.3.2, 4.3.4 and 4.3.5, respectively. Bioavailability parameters in female group have been

compared with male group by applying t-test in Table 4.3.3 and Table 4.3.6. Similarly cefspan was

compared with ceforal-3 using t-test in Table 4.3.7 and Table 4.3.8. A statistical comparison of

bioavailability parameters of two brands of cefixime in both genders was computed by applying ANOVA

and DMR test (Table 4.3.9).

4.3.1 Bioavailability of cefspan:


As shown in Table 4.3.1, after oral administration of 400 mg cefspan capsule in female

volunteers, the mean±SE of maximum concentration (Cmax), 2.24±0.23 µg/ml, was achieved at the peak

concentration time (Tmax) of 4.05±0.35 hr with area under time versus concentration curve (AUC) of

27.12±2.25 µg.hr/ml and Area under first moment curve (AUMC) of 208.99±18.47 µg.hr2/ml as the

mean±SE values. Mean±SE residence time (MRT) observed was 7.69±0.20 hr.


As given in Table 4.3.2, maximum concentration (2.93±0.24 µg/ml) of cefspan administered in

males was achieved at 4.11±0.16 hr, as mean±SE. Average area under the plasma concentration-time

curve (AUC) was observed 36.58±3.10 (mean±SE) µg.hr/ml. The mean±SE AUMC and MRT values

were 282.95±23.11 µg.hr2/ml and 7.79±0.28 hr, respectively.

163


Table 4.3.3 represents the gender difference for cefspan. It can be seen that mean±SE values of

AUC in females (27.12±2.25 µg.hr/ml) was significantly (P < 0.05) different than its respective value

(36.58±3.10 µg.hr/ml) in males. Other bioavailability parameters i.e. Cmax, Tmax, AUMC and MRT in

female and male subjects remained non significantly (P > 0.05) different from their respective values.

164

Table 4.3.1: Mean±SE parameters for bioavailability of cefspan following a single oral

administration 400 mg in 10 adult healthy female subjects.

Subject No. Cmax Tmax AUC

(µg.hr/ml)

AUMC

(µg.hr2/ml)

MRT

(µg/ml) (hr) (hr)

1

3.01

4.39 36.53 269.00 7.375

2

2.81

2.88 31.84 250.70 7.88

3

1.53

4.01 17.23 123.60 7.17

4

1.43

4.25 18.11 146.50 8.09

5

2.71

2.80 27.52 175.90 6.39

165

6

1.72

4.75 22.95 176.60 7.69

7

1.72

5.43 24.30 194.30 7.99

8

1.78

4.15 24.35 188.60 7.75

9

3.53

2.30 38.16 299.90 7.86

10

2.12

5.53 30.24 264.80 8.76

Mean±SE

2.24±0.23

4.05±0.35 27.12±2.25 208.99±18.47 7.69±0.20

Table 4.3.2: Mean±SE parameters for bioavailability of cefspan following a single oral

administration 400 mg in 10 adult healthy male subjects.

Subject

No.

Cmax Tmax AUC AUMC MRT

(µg/ml) (hr) (µg.hr/ml) (µg.hr2/ml) (hr)

29.94 258.80 8.64

166

1 2.23 3.98

2

3.50

4.68 42.94 344.60 8.03

3

4.35

4.18 55.63 390.20 7.03

4

2.66

4.47 37.95 340.60 8.97

5

2.58

3.69 30.26 229.70 7.59

6

3.25

5.14 42.05 343.10 8.16

7

1.99

3.93 22.79 163.70 7.19

8

3.23

3.59 39.47 311.40 7.89

9

1.97

3.95 24.91 210.60 8.45

10

3.52

3.51 39.83 236.80 5.95

Mean±SE

2.93±0.24

4.11±0.16 36.58±3.10 282.95±23.11 7.79±0.28

167

Table 4.3.3: Mean±SE parameters for bioavailability of cefspan following a single oral administration 400 mg in healthy adult female and male subjects.

Parameters

Units

Female

Male

Cmax

µg/ml 2.24±0.23 NS 2.93±0.24

Tmax

hr 4.05±0.35 NS 4.11±0.16

AUC

µg.hr/ml 27.12±2.25* 36.58±3.10

AUMC

µg.hr2/ml 208.99±18.47 NS 282.95±23.11

MRT

hr 7.69±0.20 NS 7.79±0.28



168

Table 4.3.4: Mean±SE parameters for bioavailability of ceforal-3 following a single oral

administration 400 mg in 10 adult healthy female subjects.

Subject

No.



1

1.78

3.67 27.1 181.50 6.69

2

3.13

2.19 26.08 165.90 6.36

3

2.33

2.87 24.8 172.90 6.97

4

1.74

3.81 18.93 131.80 6.96

5

2.78

3.48 28.65 190.90 6.66

6

2.07

3.38 21.57 132.60 6.15

7

2.05

4.42 26.44 193.90 7.34

8

1.59

4.05 19.45 153.60 7.89

9

1.64

5.23 21.4 163.70 7.65

169

10

1.75

5.61 25.42 207.60 8.17

Mean±SE

2.08±0.16

3.87±0.32 23.99±1.07 169.44±7.99 7.09±0.21

Table 4.3.5: Mean±SE parameters for bioavailability of ceforal-3 following a single oral

administration 400 mg in 10 adult healthy male subjects.

Subject

No.



1

2.02

3.59 26.48 226.80 8.57

2

2.48

4.67 30.66 226.30 7.38

3

1.93

4.25 23.12 158.00 6.84

4

1.97

4.35 26.87 233.80 8.70

63.42 516.50 8.14

170

5 4.12 5.24

6

1.49

2.70 12.69 75.55 5.95

7

1.87

2.77 24.15 203.90 8.45

8

2.56

3.42 32.55 250.80 7.71

9

2.49

4.38 31.42 258.30 8.22

10

4.44

4.12 58.6 491.30 8.39

Mean±SE

2.54±0.31

3.95±0.26 32.99±5.01 264.13±43.42 7.83±0.28

171

Table 4.3.6: Mean±SE parameters for bioavailability of ceforal-3 following a single oral administration 400 mg in healthy adult female and male subjects.

Parameters

Units Female

Male

Cmax

µg/ml 2.08±0.16 NS 2.53±0.31

Tmax

hr 3.87±0.32 NS 3.95±0.26

AUC

µg.hr/ml 23.99±1.07* 32.99±5.01

AUMC

µg.hr2/ml 169.44±7.99 * 264.13±43.42

MRT

hr 7.09±0.21 NS 7.83±0.28



172

Table 4.3.7: Mean±SE parameters for bioavailability of cefspan and ceforal-3 following a single oral administration 400 mg in healthy adult female

subjects.

Parameters

Units Cefspan

Ceforal-3

Cmax

µg/ml 2.24±0.23 NS 2.08±0.16

Tmax

hr 4.05±0.35 NS 3.87±0.32

AUC

µg.hr/ml 27.12±2.25 NS 23.99±1.07

173


Table 4.3.8: Mean±SE parameters for bioavailability of cefspan and ceforal-3 following a single oral administration 400 mg in healthy adult male

subjects.

AUMC

µg.hr2/ml 208.99±18.47 NS 169.44±7.99

MRT

hr 7.69±0.20 NS 7.09±0.21


Ceforal-3

174


Cmax

µg/ml 2.93±0.24 NS 2.53±0.31

Tmax

hr 4.11±0.16 NS 3.95±0.26

AUC

µg.hr/ml 36.58±3.10 NS 32.99±5.01

AUMC

µg.hr2/ml 282.95±23.11 NS 264.13±43.42

MRT

hr 7.79±0.28 NS 7.83±0.28

175

Table 4.3.9: Mean±SE parameters for bioavailability of cefspan and ceforal-3 following a single oral administration 400 mg in healthy adult female and

male.

Parameter Units

Female Male


Cmax

µg/ml 2.24±0.23 AB 2.08±0.16 B 2.93±0.24 A 2.53±0.31 AB

Tmax

hr 4.05±0.35 A 3.87±0.32 A 4.11±0.16 A 3.95±0.26 A

AUC

µg.hr/ml 27.12±2.25 BC 23.99±1.07 C 36.58±3.10 A 32.99±5.01 AB

AUMC

µg.hr2/ml 208.99±18.47 AB 169.44±7.99 B 282.95±23.11 A 264.13±43.42 A

176

Mean values followed by different letters in a row indicate statistically significant (P < 0.05) difference.

MRT

hr 7.69±0.20 A 7.09±0.21 A 7.79±0.28 A 7.83±0.28 A

177

4.3.2 Bioavailability of ceforal-3:


Table 4.3.4 indicates that after oral administration of ceforal-3 in female subjects, mean±SE Cmax of

2.08±0.16 µg/ml was attained at Tmax of 3.87±0.32 hr. Mean±SE values of AUC and AUMC of ceforal-3 in

females were 23.99±1.07 µg.hr/ml and 169.44±7.99 µg.hr2/ml, respectively, with mean±SE MRT of

7.09±0.21 hr.


Table 4.3.5 shows that the mean±SE values of maximum concentration of ceforal-3 in plasma (Cmax),

time to attain Cmax (Tmax), area under the plasma drug concentration versus time curve (AUC), Total Area

under the First Moment Curve (AUMC) and Mean Residence Time (MRT) for ceforal-3 administered in

healthy male subjects were 2.54±0.31 µg/ml, 3.95±0.26 hr, 32.99±5.01 µg.hr/ml,264.13±43.42 µg.hr2/ml

and7.83±0.28 hr. Data has been represented in Table 4.3.5.


Table 4.3.6 represents bioavailability parameters of ceforal-3 in female and male healthy subjects.

The Table indicated that significant (P < 0.05) gender variation for ceforal-3 was found only in values of

AUC (23.99±1.07 µg.hr/ml in females versus 32.99±5.01µg.hr2/ml in males) and AUMC (169.44±7.99

µg.hr/ml in females versus 264.13±43.42 µg.hr2/ml in males). However, the other parameters (Cmax

2.08±0.16 µg/ml versus 2.53±0.31 µg/ml, Tmax 3.87±0.32 hr versus 3.95±0.26 hr and MRT 7.09±0.21 hr

versus 7.83±0.28 hr in females and males, respectively.) showed non significant (P > 0.05) gender

variation.

4.3.3 Bioavailability of cefspan and ceforal-3:


As evident from Table 4.3.7, all bioavailability parameters of cefspan and ceforal-3, Cmax, Tmax, AUC,

AUMC and MRT, in female subjects did not show brand variation and were statistically non-significant (P >

0.05).


Table 4.3.8 indicates that all respective bioavailability parameters of cefspan and ceforal-3 in male

subjects were non-significantly (P > 0.05) different from each other. Like female subjects, male subjects did

not show brand variation forcefspanandceforal-3.

178

4.3.3.3 Gender variation of cefspan and ceforal-3:

For the purpose of gender variation, results of cefspan and ceforal-3in female and male subjects have

been compared in Table 4.3.9. Mean±SE Tmax and MRT values of cefspan and ceforal-3 in female and male

subjects did not show gender variation and were non-significantly (P > 0.05) different in female and male

subjects. Statistically significantly (P ˂ 0.05) mean±SE Cmax values were found for cefspan in males

(2.93±0.0.24µg/ml) and ceforal-3 in females. However, the highest value of Cmax was found for cefspan in

males followed by in descending order for ceforal-3 in males, cefspan in females and ceforal-3 in females.

Similarly, mean±SE values of AUC for cefspan and ceforal-3 in male and female subjects, respectively, were

found significantly (P < 0.05) different. However, the highest AUC value was found in cefspan for male

(36.58±3.10 µg.hr/ml), those of intermediate for ceforal-3 in males (32.99±5.01 µg.hr/ml) and for cefspan in

females (27.12±2.25 µg.hr/ml) and the lowest one forceforal-3 in females (23.99±1.07 µg.hr/ml). The non-

significantly (P > 0.05) different AUMC values of cefspan and ceforal-3 in males (282.95±23.11 µg.hr2/ml

and 264.13±43.42 µg.hr2/ml) were significantly (P < 0.05) dissimilar to the value of ceforal-3

(169.44±7.99µg.hr2/ml)in females and non-significantly (P > 0.05) different from the value of cefspan

(208.99±18.47 µg.hr2/ml) in females. Nevertheless, the highest value of AUMC was noted for cefspan in

males and lowest one for ceforal-3 in females with intermediate values forceforal-3 in males and cefspan in

females.

4.4 Bioequivalence Studies:

The results regarding bioequivalence of two brands of cefixime i.e. ceforal-3 as test and cefspan as

reference following400 mg oral administration of these two brands in ten healthy adult female and male

subjects with a washout period of seven days have been presented as follows:

4.4.1 Bioequivalence of ceforal-3 and cefspan in female and male subjects:

The parameters of AUC and Cmax of two cefixime brands, cefspan (reference) and ceforal-3(test),

were used to calculate bioequivalence by measuring their relative bioavailability. In healthy adult female

subjects, mean Cmax values observed for test and reference products were2.08µg/ml and 2.24µg/ml,

respectively, with T/R ratio of 0.9286.The AUC values for test and reference formulations were

27.12µg.hr/ml and 23.98µg.hr/ml, respectively, with the ratio of 0.8842 (Table 4.4.1).

In healthy adult male subjects, the Cmax values were 2.54µg/ml and 2.93 µg/ml and the AUC

values were 32.99µg.hr/ml and 36.58µg.hr/ml for test and reference brands, respectively (Table 4.4.2).

The calculated values for ratio of test to reference were 0.9019 for means of Cmax and 0.8669 for means of

AUC.

179

The mean values of Cmax for test and reference brands were non significantly (P > 0.05) different and

similarly respective test and reference values for AUC did not show any significance (P < 0.05) both in

female as well as in male subjects. The relative bioavailability values, based on Cmax (rate of absorption)

and AUC (extent of absorption), in females and males were within the range of 80-125% which are

acceptable for bioequivalence (Table 4.4.1 and Table 4.4.2).

Table 4.4.1: Relative bioavailability for AUC and Cmax of ceforal-3 and cefspan formulations in

females.

Parameter Ceforal-3 (T) Cefspan (R) Ratio (T/R)

Relative

Bioavailability

Statistical

Comparison

Cmax

(µg/ml) 2.08 2.24 0.9286 92.86% NS

AUC

(µg.hr/ml) 23.98 27.12 0.8842 88.42% NS

NS: Non-Significant (P > 0.05)

Table 4.4.2: Relative bioavailability for AUC and Cmax of ceforal-3 and cefspan formulations in

males.

Parameter

Ceforal-3

(T) Cefspan (R) Ratio (T/R)

Relative

Bioavailability

Statistical

Comparison

Cmax

(µg/ml) 32.99 36.58 0.9019 90.19 NS

180

AUC

(µg.hr/ml) 2.54 2.93 0.8669 86.69 NS

NS: Non-Significant (P > 0.05)

181

CHAPTER V

DISCUSSION

Pharmacokinetics and bioequivalence of two brands of cefixime capsule were investigated

following a single oral administration of 400 mg capsule to healthy adult female and male human

subjects. The plasma concentrations of cefixime at various time intervals after oral dose have

been used for describing pharmacokinetic and bioavailability parameters and the results thus

obtained are discussed:

5.1 Plasma concentrations:

During the course of antimicrobial therapy an antibiotic must maintain a certain

therapeutic level or minimum inhibitory concentration (MIC) in plasma. The recommended MIC

for cefixime has been reported in the range of 0.06-1.00 µg/ml (Knapp et al., 1988).

5.1.1 Plasma concentration of cefixime:

In females an upper limit of cefixime MIC was maintained in plasma for 12 hours after

administration of cefspan. The concentration observed after 12 hours of sampling following oral

administration of ceforal-3 in healthy females was less than the upper limit of cefixime MIC

(Table 4.1.4). Maximum plasma concentrations for both brands were observed at 4 hours of

sampling after oral administration in females. After maximum drug level, a progressive decline

in plasma drug concentration was observed. Plasma drug levels did not fall below the lower MIC

limit even after 24 hours of sampling in females (Table 4.1.7). At the last (24 hour) sampling

time of cefixime in females, the plasma concentration observed was 2-3 folds higher than the

lowest MIC limit.

Table 4.1.8 showed that an upper limit of cefixime MIC was maintained in male’s plasma

for more than 12 hours. However plasma levels of the drug did not fall below the lower limit of

MIC even after 24 hours of drug administration in males. So both brands, after a single oral

administration in males, maintained their therapeutic levels till last sampling time. Once

maximum concentration was achieved in plasma, drug level declined progressively, thereafter.

182

Thus cefspan and ceforal-3 both after a single oral administration in female and male healthy

volunteers, maintained their therapeutic levels in plasma till last sampling time of 24 hours. A

progressive decline in the cefixime level was observed in both genders after attaining the

maximum plasma drug concentration. However, lower plasma concentrations with shorter

duration for maintenance of therapeutic concentrations of cefixime in human subjects have been

reported in earlier studies (Brittain et al., 1985; Kees et al., 1990; Westphal et al., 1993; Liu et

al., 2002; Asiri et al., 2005).

5.2 Pharmacokinetics:

The pharmacokinetic parameters determined in the present study were best described by

one compartment open model, using a computer program, MW/PHARM version 3.02 by F.

Rombout, in cooperation with University Centre for Pharmacy, Department of Pharmacology and

Therapeutics, University of Gronigen & Medi/Ware, copy right 1987-1991. Least Square

Regression Analysis was applied to discriminate the best model and Correlation Coefficient was

taken as measure of goodness-of-fit.

Pharmacokinetics behavior of orally administered two brands of cefixime, cefspan and

ceforal-3, has been described in terms of one compartment model in human being.

Pharmacokinetic parameter results of Cefspan and Ceforal-3 capsules following single oral dose

of 400 mg in healthy female and male subjects have been discussed below:

5.2.1 Pharmacokinetics of cefixime:

The biological half life is the time required for 50 percent of the drug to be eliminated

from the body after distribution equilibrium has been attained. It is the time required for a plasma

concentration of a drug to reduce by one-half. Longer half life indicates delayed elimination of

drug and shorter half-life shows rapid elimination from the body (Baggot, 1977). Mean±SE half

life values, 3.99±0.54 and 3.12±0.39 hours, in healthy female subjects and 5.01±0.61 and

4.72±0.72 hours in healthy male subjects were observed after oral administration of cefspan and

ceforal-3, respectively. These half life values were found corresponding to the values, 3.5 hours and

4.2 hours, after 400 mg oral administration of cefixime in healthy young and elderly subjects,

respectively (Baltimore, 2005), 4.9 hours after intravascular 50 mg/kg administration of cefepime

in neonates (Capparelli et al., 2005), 4 hours in adult male volunteers administered with 400 mg

183

cefixime (Kalman and Steven, 1990), 3.09 hours in healthy female and male volunteers after

administration of 200 mg cefixime (Yi et al., 1995) and 3.5 hours and 4 hours following

intravenous administration of cefotetan and ceftizoxime, respectively, in healthy female subjects

(Bergan, 1987 and Deeter et al. 1990). However, shorter half life values have been reported as

1.50 hours and 1.89 hours after 1 g intravenous and intramuscular administration of ceftazidine,

respectively, in female subjects (Sommers et al., 1983), 1.32 hours and 1.35 hours after 1 gram

intravenous administration of cefotaxime and cefoperazone, respectively, in women after 2 -3

postpartum days (Charles and Bryan, 1986), 1.18 hours after 1gmcefotaximeadministration in

healthy adult subjects (Standiford et al., 1982), 2.6 hours following 1g intravenous administration

of cefoperazone in human subjects (Sootornpas et al., 2011) and 3 hours after administration of

400 mg cefixime in males (Low, 1995) and in another study 3 hours after its multiple doses of 50,

100, 200 and 400 mg in healthy male subjects (Brittain et al., 1985).Further, in present study half

life values in healthy adult female and male subjects were shorter than 6.2 hours and 6.77 hours

following administration of 2 g ceftriaxone infusion in healthy volunteers and pregnant patients,

respectively (Bourget et al., 1993), 8.16 hours and 7.60 hours in healthy women after

administration of 250 mg ceftriaxone intravenously and intramuscularly, respectively (Robert et

al., 2001) and 5.4 to 10.9 hours in healthy adult males following 1 g intravenous administration

of ceftriaxone (Kalman and Steven, 1990). The elimination half life of cefixime in local human

subjects have mostly been found longer than those in their foreign counterparts (Table 2.1). It

has been appreciated that half life is a derived parameter which changes as a function of both

clearance and volume of distribution (Gibaldi, 1984). Thus longer half life values in present

study may be attributed to the higher value of Vd and lower values of β and ClB than most

reported values in the literature and converse is also true (Table 2.1).

The apparent volume of distribution (Vd) relates the drug concentration in plasma to the total

amount of the drug in the body after distribution equilibrium has been attained (Gibaldi and Perrier,

1982). It is the theoretical concept that relates the administered dose with the actual initial

concentration present in the circulation (Smith et al., 2001). The more than unity mean±SE values

of volume of distribution recorded in male adults (1.10±0.15 l/kg for cefspan and 1.29±0.21 l/kg for

ceforal-3) and in female adults (1.38±0.22 l/kg for cefspan and 1.36±0.17 l/kg for ceforal-3) of

present investigations reflect excellent tissue penetration of the drug. These values were found to be

higher than the values, 0.26 and 0.5 l/kg, reported in their foreign counterparts following oral

184

administration of 200 mg and 400 mg cefixime, respectively (Faulkner et al., 1987), 0.23 l/kg

following intravenous administration of cefotaxime in healthy adult subjects (Standiford et al.,

1982) and 0.3 l/kg after intravenous administration of 200 mg cefixime (Ziv et al., 1995).Further,

lower values have been reported in women during postpartum period after cesarean section, 0.18

l/kg (Gonik et al., 1986), in female patients of cystic fibrosis, lower respiratory tract infections

and sepsis after administration of cefepime, 0.32 l/kg, 0.22 l/kg and 0.47 l/kg, respectively

(Ambrose et al., 2002), in young and elderly females following intravenous administration of

1gm cefepime, 0.21 l/kg and 0.24 l/kg, respectively (Barbhaiya et al., 1992b). The values of Vd in

present study were found similar to 1.71 l/kg after 200 mg intravenous administration (Duverene et

al., 2012), 1.1 l/kg after 400 mg oral (Guay et al., 1986) and 1.112 l/Kg after 400 mg oral

administration of cefixime in adult male subjects (Guay et al., 1986).However, higher values of

2.2 l/kg and 2.8 l/kg were recorded in dogs following oral doses of 6.25 mg/kg and 25 mg/kg

cefixime, respectively (Bialer et al., 1987) and 8.8 l/kg was recorded in healthy adult males after

parenteral administration of 1 g cephapirin (Kalman and Steven, 1990). Further, higher values

have been reported as 11.7 l/kg and 12.54 l/kg in healthy and pregnant females, respectively,

after infusion of 2gmceftriaxone (Bourget et al., 1993). In the present study, the values of

volume of distribution in healthy subjects were found greater than most values reported in

literature (Table 2.1).The greater value of Vd for cefixime indicates its excellent penetration into

the tissues. Besides intra and inter species biological variations, a possible explanation for the

higher value of Vd in the present study may be linked to the lower extrapolated zero time drug

concentration (B) as compared to that of its higher values in above cited studies.

Total body clearance represents the sum of metabolic and excretory processes and is the

volume of blood completely cleared of a drug in a unit time. It is the sum of all processes which

contributes towards elimination of drug from the body. The mean±SE total body clearance in adult

female subjects (0.27±0.02 l/hr/kg and 0.31±0.02 l/hr/kg for cefspan and ceforal-3, respectively)

and in adult male subjects (0.16±0.02 and 0.21±0.04 l/hr/kg for cefspan and ceforal-3, respectively)

of present study were comparable to 0.28 l/hr/kg in neonates administered with 50 mg/kg

ceftriaxone (Mulhall et al., 1985) and 0.14 l//hr/kg (Guay et al., 1986) and 0.26 l/h/kg (Faulkner et

al., 1988) in healthy adult subjects receiving 400 mg cefixime orally. The values of total body

clearance, 0.24 l/hr/kg and 0.31 l/hr/kg, observed in dogs after intravenous infusion of cefixime at

dose rate of 6.25 mg/kg and 25 mg/kg, respectively (Bialer et al., 1987) have also been found

185

corresponding to the ClB values of cefixime in healthy subjects of present study. The higher

values of ClB have been reported in adults as3.55 l/hr/kg following 200 mg intravenous injection of

cefixime (Duverene et al., 2012), 4.5 l/hr/kg in neonates after administration of 30 mg/kg cefoxitin

(Regazzi et al., 1983), 6.69 l/hr/kg, 9.25 l/hr/kg and 9.87 l/hr/kg in children following dose of 10

mg/kg, 15 mg/kg and 20 mg/kg cefixime, respectively (Alshare, 1999) and 5.38 l/hr/kg for 1000

mg intravenous cefoperazone in women 2-3 days after postpartum (Charles and Bryan, 1986).

However, lower values were observed in healthy humen as 0.02 l/hr/kg, 0.25 l/hr/kg , 0.3 l/hr/kg

and 0.35 l/hr/kg for respective multiple doses of 50 mg, 100 mg, 200 mg and 400 mg cefixime

(Brittain et al., 1985). Further, lower body clearance has been reported as0.03 l/hr/kg for 200 mg

cefixime administered orally in patients suffering from respiratory tract infections (Guay et al.,

1986) and 0.07 l/hr/kg in women following intravenous administration of 2 gm cefoperazone

after surgical delivery (Gonik et al., 1986).

Although in present study the pharmacokinetic parameters of cefixime in local female and

male human being have been found similar, lower and higher than the reported values in literature

yet it may be noted that B, β and ClB remained lower while t1/2 β and Vd remained higher than most

respective values in their foreign counterparts and animals (Table 2.1). A lower total body

clearance (ClB) in local subjects of present study than most reported values in literature may be

attributed to lower values of β as compared to its respective higher reported values (Table 2.1)

while converse is also true (Javed et al., 2003) . It has been reported that cefixime is excreted

unchanged in urine (Faulkner et al., 1988; Barre, 1989; Westphal et al., 1993; Baltimore, 2005).

Lower total body clearance may also be related to reabsorption of major unionized moiety of

acidic cefixime (pKa=2.5) in acidic human urine (pH=5.5-6.5) available at kidney tubular level

(Majid, 2014 and Nisar, 2014). Since the clearance parameter comprises a volume as well as a rate

component (Baggot, 1977), lower total body clearance of cefixime in local subjects may also be

indicative of longer half life and higher volume of distribution of the drug in present study. Thus

the alteration in either ClB or Vd may affect the half life (Prescott and Baggot, 1988). The

differences regarding pharmacokinetic parameters of local subjects of present study may also be

attributed to environmental and genetic variations when compared with those of their foreign

counter parts (Javed et al., 2003; Javed et al., 2009a,b; Hussain et al., 2014).

186

The half life of a drug is a derived parameter that changes as a function of both clearance

and volume of distribution. The apparent volume of distribution of a drug is a function of the

volume of tissues in which drug distributes, partition coefficient of drug between tissues and

circulatory blood, the blood flow to the tissues and binding of drugs to the plasma and tissue

proteins. The total body clearance depends upon blood flow to the organ, fraction of unbound drug

in blood and maximal ability of the organ to remove the drug. Most of these factors are under

environmental and genetic control (Eckland and Danhof, 2000; Javed et al., 2009a,b; Hussain et al.,

2014).

5.3 Bioavailability:

The fraction of the administered dose that reaches the systemic circulation is called

bioavailability. Bioavailability refers both to the rate of the drug absorption and to the extent of

absorption. It is the one of many factors that determines the relation between drug dosage and

intensity of action. Bioavailability is the function of Cmax, Tmax and AUC where Tmax is closely

related to the absorption rate and Cmax depends upon both the extent and rate of drug absorption.

However, drug absorption continues after Cmax has been attained. More is the drug absorption,

higher is the total area under plasma concentration versus time curve (AUC) which represents the

extent of drug absorption. The higher AUC results in the higher bioavailability of the drug. An

increased absorption may lead to increased distribution too. The rate and extent of the absorption

depends upon the pH of the environment, drug solubility, biotransformation, absorption at the

intestinal level, gastric emptying time, gastric motility and systemic circulation toward the

absorption sites. When a drug product shows poor systemic availability, it usually becomes

necessary to distinguish between dosage form and physiologically modified bioavailability

(Krebs, 2001; Parada and Aguilera, 2007).

The differences of Cmax, Tmax and AUC values of current study to that of literature values

have been shown in Table 2.3. Bioavailability parameters of cefixime brands, cefspan and

ceforal-3, were analyzed after single oral administration 400 mg in healthy female and male

subjects and the results were discussed below:

5.3.1 Bioavailability of cefixime:

187

The maximum plasma concentration (Cmax) of cefspan (2.24±0.23 µg/ml and 2.93±0.24

µg/ml) and ceforal-3 (2.08±0.16 µg/ml and 2.53±0.31 µg/ml) following oral dose in healthy adult

female and male subjects, respectively, were smaller than 13.4 and 11.7 µg/ml in healthy female

subjects following oral intake of 500 mg cefaclor with water and juice, respectively (Li et al., 2009)

and 25.2μg/ml, 110μg/ml and 574 µg/ml in neutropenic mice following 25 mg/kg , 100 mg/kg

and 400 mg/kg administration of ceftolozane (Craig and Andes, 2013). The peak plasma

concentrations observed for cefspan and ceforal-3 were found also to be lesser than reported

values in healthy male volunteers as 3.38 μg/ml and 3.45 μg/ml for winex and suprax 200

mg/10ml suspension, respectively (Asiri et al., 2005), 4.74 μg/ml and 4.96 μg/ml for loprax and

reference cefixime 400 mg capsules, respectively (Zakeri et al., 2008), 3.38μg/ml and 3.29 μg/ml

for Tablet and capsule, respectively, of cefixime 200 mg given orally (Lan-Ying et al., 2004) and

6.3 μg/ml and 13.7 μg/ml after oral intake of 1 gram of cefuroxime and cefadroxil, respectively,

in healthy subjects (Kalman and Steven, 1990). The values of Cmax observed in the present study

were found corresponding to 2.17 μg/ml for oral cefixime 400 mg (Jieying et al., 1996), 2.63

μg/ml and 3.85 μg/ml for 200 mg and 400 mg cefixime Tablets, respectively (Brittain et al.,

1985) and 2.317 mg/L and 2.287 mg/L for two brands of 200 mg cefixime capsules, respectively

(Ying et al., 2003) in healthy male subjects. The results were also comparable to 2.95 and 2.43

µg/ml following oral dose of 200 mg cefixime Tablet and syrup, respectively, in healthy female and

male volunteers (Kees et al., 1990) and 2.64 µg/ml following administration of cefixime in patients

of respiratory tract infections (Yi et al., 1995). However, the Cmax values of both brands of cefixime

used in healthy females and males of present study were larger than 0.64 µg/ml and 1.15 µg/ml

(Motohiro et al., 1986) in children administered with 1.5 mg/kg and 3 mg/kg cefixime,

respectively,0.7 µg/ml, 1.2 µg/ml and 2.1 µg/ml following twice a day oral administration of 50

mg, 100 mg and 200 mg cefixime, respectively, in healthy volunteers (Nakashima et al., 1987), 2

µg/ml in healthy adult subjects after oral intake of 300 mg cefdinir (Kalman and Steven, 1990),

0.89 µg/ml in neonates following parental administration of 50 mg/kg cefepime and 1.26 µg/ml

for 50 mg cefixime granules and 1.16 µg/ml for 50 mg capsule of cefixime administered in

human subjects (Motohiro et al., 1986).

The time of the first occurance of Cmax, called Tmax, was found to be 4.05±0.35 hours and

3.87±0.32 hours in healthy female subjects and 4.11±0.16 hours and 3.95±0.26 hours in healthy

male subjects of present study after oral administration of cefspan and ceforal-3 400 mg

188

capsules, respectively. These values were similar to the Tmax, 4 hours, observed after oral

administration of 200 mg cefixime in condition of respiratory tract infection (Yi et al., 1995), 3.3

to 3.5 hours noted after oral administration of 200 mg in healthy state (Kees et al., 1990), 3.7

hours and 3.3 hours for cefixime 200 mg administered in fasting and non-fasting condition,

respectively (Yaoguo et al., 1994), 4 hours for 400 mg Tablet of cefixime in healthy male

volunteers (Healy et al., 1989; Montay et al., 1991) and 4.7 hours (Lan-ying et al., 2004) and 3.7

hours (Duverene et al., 2012) after administration of 200 mg cefixime Tablets in healthy human

volunteers. The time to attain maximum drug concentration (Tmax) in present study were longer

than 0.5 hours and 1.0 hours after administration of 2 g infusion of ceftriaxone in healthy subject

and pregnant patients, respectively (Bourget et al., 1993), 2 hours after administration of Cis and

Trans isomers of cefprozil in lactating females (Shyu et al., 1992), 1.25 hours in females

following 500 mg oral administration of cefaclor (Li et al., 2009), 2 hour after administration of

cefixime 400 mg in healthy males (Low, 1995), 0.25 hours in mice injected with ceftolozane

(Craig and Andes, 2013) and 1.44 hours for cefroxadine (Kang et al., 2006), 1.9 hours for 1 g I/V

cefoperazone (Sootornpas et al., 2011) and 1.5 hours for 1 g I/M ceftriaxone (Meyers et al.,

1983) after administration in healthy adult males. The value of 5.2 hours for cefixime 400 mg

administered orally in healthy men (Liu et al., 2005) and 6.7 hours for cefixime 400 mg

administered in healthy male volunteers (Stone et al., 1988) were found longer than the values

observed in present study.

The area under the plasma concentration-time curve (AUC) is a measure of extent of drug

absorption and reflects the availability of drug in systemic circulation (Shargel and Yu., 1999)

while total area under the first moment of a plasma concentration-time profile (AUMC) is the

total area under the curve resulting from a plot of the time and product of drug concentration and

time. The AUMC is used for assessing the extent of distribution i.e. volume of distribution at

steady state and the persistence of drug in the body (Kwon, 2001). The AUC values in females,

27.12±2.25 µg.hr/ml and 23.99±1.07 µg.hr/ml, and in males, 36.58±3.14 µg.hr/ml and

32.99±5.01 µg.hr/ml were investigated following oral administration of cefspan and ceforal-3,

respectively. The mean±SE values of AUMC for cefspan and ceforal-3 were 208.99±18.47

µg.hr2/ml and 169.44±7.99 µg.hr2/ml, respectively, in females and 282.95±23.11 µg.hr2/ml and

264.13±43.42 µg.hr2/ml in males, respectively. The AUC values of present study were found

similar to 26 µg.hr/ml and 23.6 µg.hr/ml following administration of 200 mg oral solution and

189

200 mg capsule, respectively, in healthy volunteers (Faulkner et al., 1988), 25.8 µg.hr/ml after

administration of 400 mg cefixime in healthy volunteers (Jieying et al., 1996) and 30.22

µg.hr/ml in women intravenously administered with 1 g cefotaxime 2-3 days after postpartum

(Charles and Bryan, 1986). However, AUC values in present study were found smaller than

155.7 µg.hr/ml following administration of 2 g ceftriaxone intravenously (Pletz et al., 2004), 172

µg.hr/ml and 218 µg.hr/ml of cefepime in young and elderly female subjects, respectively

(Barbhaiya et al., 1992b), 179.8 µg.hr/ml and 169.4 µg.hr/ml for ceftazidime 1000 mg

administered intravenously and intramuscularly, respectively, in female subjects (Sommers et al.,

1983), 34.9 µg.hr/ml and 49.5 µg.hr/ml following 400 mg oral dose of cefixime in young and

elderly person, respectively (Baltimore, 2005), 40 µg.hr/ml (Guay et al., 1986) and 38.3 µg.hr/ml

(Healy et al., 1989) after administration of 400 mg Tablet in healthy adult males. Further, the

AUC values of present investigations remained higher than AUC of 15.92 µg.hr/ml and 15.97

µg.hr/ml (Yu-fei et al., 2004), 19.91 µg.hr/ml and 19.09 µg.hr/ml for two brands of cefixime,

respectively, in healthy male volunteers, (Min-ji et al., 2004) 13.3 µg.hr/ml after parenteral

administration of ceftolozane in mice (Craig and Andes, 2013), 6.2 µg.hr/ml in lactating mothers

administered with cefprozil (Shyu et al., 1992) and 2.91, 3.13 and 3.01 µg.hr/ml in group of

healthy female and male subjects administered with cefixime 200 mg Tablet, syrup and dry

suspension, respectively (Kees et al., 1990).

Mean residence time (MRT) is the statistical moment analogy to drug half life. It

provides information related to the time required to eliminate 62.8% of the dose (Gibaldi, 1984).

It is helpful in measuring how longer a drug substance or molecule resides in a compartment.

There are numerous drug molecules that reside in the compartment at a given time; each

molecule enters the compartment through one of the inputs and leaving through one or more of

the outputs. Each molecule may spend a different length of time in the compartment because of

input and output distribution times; moreover there also exists a distribution of time length with

which the drug molecule stays in the compartment. The mean±SE values of MRT for cefspan

and ceforal-3 orally administered in females were 7.69±0.20 hours and 7.09±0.21 hours,

respectively. Mean±SE values of MRT in case of males were 7.79±0.28 hours and 7.83±0.28

hours for cefspan and ceforal-3, respectively. The present MRT values were corresponding to the

literature cited value, 7.47 hr after oral administration of cefixime 400 mg in healthy volunteers

(Jieying et al., 1996). In current study the mean residence time (MRT) for cefixime in indigenous

190

human were shorter than the 9.1 hours for 2 g intravenous ceftriaxone in healthy male and

female subjects (Pletz et al., 2004), 17.81 hours after administration of cephradine 250 mg

capsules in healthy male volunteers (Shoaib et al., 2008), 15 hours after intravenous

administration of 1 g ceftriaxone in cardiac patients (Martin et al., 1996), 29.9 hours after

intravenous administration of ceftriaxone 2 gm in liver transplant recipients (Toth et al., 1991).

The mean residence time (MRT) of cefixime in the present study was longer than the earlier

studied values for cefpodoxime (5.7 hours) and cefixime (6.5 hours) after 400 mg oral

administration (Liu et al., 2005), for 500 mg cephalexin (1.89 hours) in female and male

volunteers (Mircioiu et al., 2007). The values of mean residence time in present study were

found longer than the most literature values in foreign counterparts (Table 2.3). The longer

values of MRT for cefixime were due to respective higher values of AUMC in present study.

In present study bioavailability parameters of Cefixime e.g. Cmax was lower while Tmax,

AUC, AUMC and MRT were higher than most respective reported values (Table 2.3).

5.4 Bioequivalence:

Bioequivalent are chemically equivalent drug products which when given in the same

dosage regimen would result in comparable bioavailability. The bioavailability of drug is

influenced by both pharmaceutical and biological factors (Wagner, 1975). The pharmaceutical

manufacturing unit can control the pharmaceutical factors, while, the biological factors are

uncontrollable. Manufacturing processes have been found to affect the bioavailability and

responses to various drugs (Curry, 1977).

Two or more drug products are bioequivalent if the parameters of rate and amount of

absorption do not show significant (P < 0.05) differences when administered under similar

conditions to human subjects and when their ratios fall between 0.80 to 1.25 (Aboulenein et al.,

2005).

5.4.1 Bioequivalence of cefixime:

191

Bioequivalence studies of generic pharmaceuticals are essential to be compared to the

reference brand products to ensure safety and conformity of these generics. The present study

showed that the test formulation of cefixime (ceforal-3 400 mg) capsule was bioequivalent to the

reference product (cefspan 400 mg) in healthy female and male subjects. Based on T/R ratio values

of AUC and Cmax, relative bioavailability in females (88.46% and 92.86%) and males (90.21% and

86.64%) were found in the range, 80 -125%, for bioequivalence of drugs (Table 4.4.1 and Table

4.4.2). Earlier, bioequivalence of local and imported products of cefixime with T/R ratio of0.1035

have been declared within the acceptance limit of 0.80-1.25 (Yu-fei et al., 2004), while, in another

study the relative bioavailability of cefixime 200 mg Tablet to capsule was 102.8% (Lan-Ying et al.,

2004). Further, Ming-Hui, (2009) observed that 200 mg cefixime Tablet was bioequivalent to 200 mg

cefixime capsule after oral administration in healthy volunteers. Consequently formulations of

cefixime, ceforal-3 as test (local brand) and cefspan as reference (international brand), were

therapeutically bioequivalent and interchangeable in female and male subjects and therefore can be

considered equally effective in medical practice. Moreover, the substitution of the reference product

(cefspan) by the less expensive, yet similarly effective test product (ceforal-3) is justified in both

genders and can be used alternatively in clinical practice.

5.5 Gender variation:

Physiologic differences existing between women and men play a role in prevalence and

outcomes of disease. Gender differences also have implications on pharmacodynamics and

pharmacokinetics of the drugs (Whitley, 2009). Sex-related differences in pharmacokinetics have

been considered as an important determinant for effectiveness (clinical) of drug therapy. The

mechanistic factors resulting in sex-specific pharmacokinetics can be divided into physiological

and molecular factors on basis of which pharmacokinetics in women may be affected when it is

compared with males (Meibohm et al., 2002; Whitley, 2009).

Amongst pharmacokinetic parameters of cefixime higher values of B and t1/2β while

lower values of β, Vd and ClB have been observed in males showing gender variation. Moreover,

bioavailability parameters e.g. Cmax, Tmax, AUC, AUMC and MRT were found to have higher

values in males also reflecting gender variation. In present study plasma concentrations in male

subjects remained high as compared to those in female subjects (Fig. 4.1.9). The higher plasma

concentrations in males may be linked to more absorption of acidic cefixime from stomach

having more acidic environment than that present in female as stomach of females secretes less

192

gastric acid (Fletcher et al., 1994; Whitley and Lindsey, 2009) than that in males due to low

chloride ion concentration in plasma (Akan et al., 2014). Consequently more unionized moiety

of cefixime having pKa value of 2.5 will be available in stomach of male which is suitable for

absorption rendering higher plasma concentrations. The higher values of Cmax, Tmax, AUC,

AUMC and MRT in males of present study than those of females may be attributed to higher

plasma concentrations as AUC is a measure of extent of drug absorption and reflects the

availability of drug in systemic circulation (Shargel and Yu., 1999) while AUMC is the total area

under the curve resulting from a plot of the time and product of drug concentration and time

reflecting persistence of drug in the body (Kwon, 2001). Further lower values of Vd in males as

compared to that in females may be linked to higher value of B in males and similarly lower

value of ClB in males is due to lower value of Vd and β in males. Further, higher value of t1/2β in

males may be due to lower value of β in males than investigated in females (Table 4.2.9). High

levels of proteins and amino acids have been reported in males as compared to females (Pigoli et

al., 2010) resulting more uric acid excretion in urine making it more acidic (Silaon et al., 1991).

Moreover, higher excretion of chloride in urine of males than in females contributes to more

acidic urine in males (Akan et al., 2014). Cefixime being an acidic drug with pKa=2.5 (Rao et

al., 2010), will be available in more acidic urine of males as unionized moiety of drug which is

suitable for absorption from kidney tubules rendering less urinary excretion in males than that in

females. Urinary excretion of cefixime will build a major portion of total body clearance which

is sum of all metabolic and excretory processes if kidney remains major pathway for excretion of

cefixime (Westphal et al., 1993). So higher clearance of cefspan and ceforal-3in females than

that present in males may be attributed to lower urinary pH in males.

Both the brands, cefspan and ceforal-3, were observed bioequivalent in females as well as

in males. The bioavailability parameters, Cmax and AUC, of both the brands were non-

significantly (P > 0.05) different in both genders. The ratio (T/R) for Cmax was 0.9286 and 0.9019

in females and males, respectively and the relative bioavailability based on AUC was 88.42 and

86.69 in female and male healthy subjects, respectively, which were in the acceptable range of

bioequivalence. So gender difference played no specific role in bioequivalence of different

brands of a drug.

193

Keeping in view the aim and hypothesis of the study differences regarding

pharmacokinetic and bioavailability of two brands of the cefixime were not observed in female

and male subjects. However, some gender variations were found to be present. So, a least

expansive local brand ceforal-3 was found bioequivalent to the most expensive multinational

brand cefspan.

5.6 Conclusions:

1. In indigenous male and female human beings, pharmacokinetic parameters of cefixime

e.g. B, β and ClB have been found to be lower while t1/2β and Vd remained higher than

most respective reported values.

2. Bioavailability parameters of cefixime e.g. Cmax was lower while Tmax, AUC, AUMC and

MRT were higher than most respective values in their foreign counterparts.

3. Higher plasma concentrations of cefixime in males than present in females show gender

variation.

4. Amongst pharmacokinetic parameters higher values of B and t1/2β while lower values of

β, Vd and ClB have been observed in males showing gender variation.

5. Higher values of ClB in females than that in males may be related to more urinary

excretion of acidic cefixime in comparatively less acidic urine in females than reported in

males.

6. Bioavailability parameters e.g. Cmax, Tmax, AUC, AUMC and MRT were found to have

higher values in males reflecting gender variation.

7. Both formulations of cefixime i.e. ceforal-3 and cefspan are bioequivalent in male and

female genders.

8. Bioequivalence clearly demonstrates that both formulations of cefixime are exchangeable

in clinical practice resulting low cost therapy in patients using locally manufactured

brand, ceforal-3.

194

CHAPTER VI

SUMMARY

The differences of environmental conditions and genetic makeup of man and animals

between drug exporting and importing countries like Pakistan necessitate the investigations of

pharmacokinetic and bioavailability of drugs in local subjects as these differences are manifested

through the variation in pharmacokinetic and bioavailability parameters. Various formulations of

the same drug may show different bioavailability and cannot be used alternatively. This serious

issue may be identified by bioequivalence studies which highlight this difference in the

bioavailability and therapeutic efficacy among formulations of same drug. So, the need of

pharmacokinetic, bioavailability and bioequivalence studies has been increased for local

population. One must consider the genetic, sexual and environmental conditions of individuals

when interpreting plasma drug concentration. Gender, genetic and environmental differences in the

pharmacokinetic, bioavailability and bioequivalence of cefixime were investigated in healthy adult

female and male subjects in this study.

Cefixime is a third generation orally acting cephalosporin, used for the treatment of

different microbial infections. Pharmacokinetics and bioequivalence of cefixime was

investigated in healthy adult female and male human subjects. After through clinical examination

healthy volunteers (n = 20), female volunteers (n = 10) and male volunteers (n = 10), were

selected for the study. Two brands, cefspan and ceforal-3, of cefixime were selected. Each

volunteer was given an oral dose of 400 mg capsule of each brand with a washout period of 7

days. In each experiment a blank blood sample was collected prior to drug administration. More

blood samples were taken with hourly interval up to 6 hours and then on 12 and 24 hours, post

medication. Concentration of cefixime in plasma samples was determined by high performance

liquid chromatographic method. The plasma concentration versus time data was best analyzed by

the one compartment open model for determination of various pharmacokinetic and bioavailability

parameters. Data was statistically analyzed by using student’s paired t-test. Where necessary,

comparison amongst parameters was carried out by applying DMR conditional to the

significance of ANOVA. For bioequivalence, estimates of extent and rate of absorption

195

comparison in terms of AUC and Cmax between the test (ceforal-3) and reference (cefspan)

brands were calculated.

Maximum concentration of cefspan in blood of female and male volunteers was

3.03±0.45 μg/ml and 4.05±0.42 μg/ml, achieved at 3 and 4 hours, respectively, indicating the

good absorption of cefspan in males. Comparatively maximum plasma concentration of ceforal-3

in females and males were observed as 3.07±0.30 μg/ml and 3.47±0.56 μg/ml, respectively, at 4

hours each. So the highest plasma cefixime concentration was observed in males administered with

cefspan and the lowest in females given ceforal-3.The plasma concentration was lower in females

throughout the sampling duration. The plasma concentration versus time data was applied on an

APO PC-Computer Program MW/PHARM version 3.02by using one compartment open model for

calculation of various parameters.

The extrapolated zero time plasma concentration of cefspan was 5.14±0.74 μg/ml and

5.94±0.78 μg/ml and of ceforal-3 was 5.31±0.57 μg/ml and 5.45±0.86 μg/ml in healthy female

and male subjects, respectively. Elimination rate constant values were 0.21±0.03 hr-1and

0.25±0.03 hr-1in females and 0.16±0.02 hr-1and 0.18±0.03 hr-1in males after oral administration

of cefspan and ceforal-3, respectively. The half life values were found 3.99±0.54 hr and

3.12±0.39 hr in local adult female subjects and 5.01±0.61 hr and 4.72±0.72 hr in healthy adult

male subjects following administration of cefspan and ceforal-3, respectively. The values of

volume of distribution in local adult female and male volunteers were 1.38±0.22 l/kg and

1.10±0.15 l/kg, respectively, for cefspan and 1.36±0.17 l/kg and 1.29±0.21 l/kg, respectively, for

ceforal-3.The total body clearance for cefspan and ceforal-3 were 0.27±0.02 l/hr/kg and

0.31±0.02 l/hr/kg, respectively, in local females and 0.16±0.02 l/hr/kg and 0.21±0.04 l/hr/kg,

respectively, in local males.

Cefspan had Cmax value of 2.24±0.23 μg/ml and 2.93±0.24 μg/ml, Tmax value of

4.05±0.35 hr and 4.11±0.16 hr, AUC value of 27.12±2.25 μg.hr/ml and 36.58±3.10 μg.hr/ml,

AUMC value of 208.99±18.47 μg.hr2/ml and 282.95±23.11 μg.hr2/ml and MRT values of

7.69±0.20 hr and 7.79±0.28 hr, in healthy female and male volunteers, respectively.The values of

AUC 23.99±1.07 μg.hr/ml and 32.99±5.01 μg.hr/ml, Cmax 2.08±0.16 μg/ml and 2.53±0.31μg/ml,

Tmax 3.87±0.32 hr and 3.95±0.26 hr, AUMC 169.44±7.99 μg.hr2/ml and 264.13±43.42 μg.hr2/ml

196

and MRT 7.09±0.21 hr and 7.83±0.28 hr were noted for ceforal-3 administered in female and

male subjects, respectively.

In indigenous male and female human beings, pharmacokinetic parameters of cefixime

e.g. B, β and ClB have been found to be lower while t1/2β and Vd remained higher than most

respective reported values. Bioavailability parameters of cefixime e.g. Cmax was lower while

Tmax, AUC, AUMC and MRT were higher than most respective values in their foreign

counterparts. Higher plasma concentrations of cefixime in males than present in females show

gender variation. Amongst pharmacokinetic parameters higher values of B and t1/2β while lower

values of β, Vd and ClB have been observed in males showing gender variation.

Higher values of ClB in females than that in males may be related to more urinary

excretion of acidic cefixime in comparatively less acidic urine in females than reported in males.

Bioavailability parameters e.g. Cmax, Tmax, AUC, AUMC and MRT were found to have higher

values in males reflecting gender variation. Both formulations of cefixime i.e. ceforal-3 and

cefspan are bioequivalent in male and female genders. Bioequivalence clearly demonstrates that

both formulations of cefixime are exchangeable in clinical practice resulting low cost therapy in

patients using locally manufactured brand, ceforal-3.

197

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APPENDICES

Appendix 1: Laboratory investigation of 10 healthy female subjects involved in

pharmacokinetic and bioequivalence study of cefixime.

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Appendix 2: Laboratory investigation of 10 healthy male subjects involved in pharmacokinetic

and bioequivalence study of cefixime.

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