DETERMINANTS OF PHARMACOKINETIC

PARAMETERSDR. JEFFREY PRADEEP RAJ,

1ST YEAR PGDEPT. OF PHARMACOLOGY, SJMC

22ND JUNE, 2015

TOPIC OVERVIEW• Pharmacokinetics (PK) Definition • PK Parameters• Drug Absorption & Bioavailability• Volume of Distribution• Biotransformation of drugs (Metabolism)• Drug elimination including Clearance & T ½ • Summary• References

PHARMACOKINETICS - DEFINITION

• Pharmacon – drug : kineticos – movement• Study that deals with movement of drugs within

the body• “Process of absorption, distribution, metabolism

(biotransformation) & elimination of drugs in the body”• Absorption & distribution - rate of onset of action;

Biotransformation & elimination - extent / duration of action

PHARMACOKINETIC PARAMETERS

DEFINITION PARAMETER

Absorption Movement of drug from site of administration into circulation

Bioavailability (F)

Distribution Pattern of scatter of specified amount of drug among various locations in the body

Volume of Distribution (Vd)

Metabolism Enzyme catalysed chemical transformation of drugs within living organism

Elimination Excretion of drug metabolites outside the body

Clearance (CL)Half Life (T ½)

ABSORPTION

Drug Factors Patient factors Bioavailability

DRUG FACTORS (1/3)• Concentration of Drug• Lipid solubility (Eg. Fentanyl)• Free movement across bio-membranes

• Crystal Form • Amorphous Novobiocin better than crystalline

form• Spray dried Fenofibrate better than crys. FFB *

* Yousaf AM et al. Effect of the preparation method on crystallinity, particle size, aqueous solubility and dissolution of different samples of the poorly water-soluble fenofibrate with HP-β-CD. Journal of Inclusion Phenomena and Macrocyclic Chemistry 2014; 81(3-4): 347-356

DRUG FACTORS (2/3)• Dosage forms – • Vehicle – water / oil• Disintegration – solid form to break-up into

individual particles• Dissolution – disintegrated particle to dissolve in

GI contents• Eg: Albendazole + hydroxy propyl β cyclodextrin

– better disintegration & dissolution*

*MN Anjana et al. Solubility and bioavailability enhancement of albendazole by complexing with hydroxy propyl β cyclodextrin. Journal of Chemical & Pharmaceutical Research. 2015; 7(4): 1131-41

DRUG FACTORS (3/3)•Particle Size • Microfined griseofulvin better than griseofulvin

• Salt Form • Salt of Weak acids – sod. Tolbutamide better than

tolbutamide• Water of hydration• Anhydrous theophylline better than hydrous form

PATIENT FACTORS (1/3)• Route of administration• Parenteral Vs Enteral – Intranasal midazolam for

seizures in children*

• Local metabolism • Insulin not available orally - degraded by

intestinal brush border enzyme peptidase• Local Binding (in SC/IM Inj)

*Kälviäinen R. Intranasal therapies for acute seizures. Epilepsy & Behav (2015); doi:10.1016/j.yebeh.2015.04.027

PATIENT FACTORS (2/3)• Local environment (PH, disease states)• Tannic acid over burnt skin - liver necrosis

• Vascularity of absorbing surface• Timolol eye drops - bradycardia while ointments

did not; drops reached vascular nasal mucosa via Nasolacrimal duct*

*Pratt NL et al. Association between Ophthalmic Timolol and Hospitalisation for Bradycardia. Journal of Ophthalmology 2015; doi:10.1155/2015/567387

PATIENT FACTORS (3/3)• Drug – drug interactions • Antacids forms complexes with tetracycline• Vit. C favours iron absorption

• Area of absorbing surface• Gentamicin - neurotoxicity in peritoneal wash*

*Varghese JM et al Pharmacokinetics of Intraperitoneal Gentamicin in Peritoneal Dialysis Patients with Peritonitis (GIPD Study). Clin J Am Soc Nephrol. 2012 Aug 7; 7(8): 1249–1256.

• Gastric emptying & GI motilityMetoclopramide BA of Digoxin ; BA Paracetomol, Propantheline – opposite effect

• GI Diseases Coeliac disease - Fat malabsorption Amoxicillin absorption Cephalexin

• FoodPhenytoin absorption better after food due to food induced bile secretion

PATIENT FACTORS SPECIFIC TO ORAL ABSORPTION

BIOAVAILABILITY (F)• Fraction of drug that reaches • Site of action (or) • Any biological fluid from which it gains access to

site of action (or)• Systemic circulation in the unchanged form

• Practical significance in low safety margin drugs (digoxin) / precise dosage control drugs (warfarin)• Bioavailability (F) % = AUC(ORAL) / AUC (IV) X 100

DETERMINANTS OF BIOAVAILABILITY

• Absorption• First Pass metabolism• P Glycoprotein efflux

pumps• Biliary excretion

AREA UNDER THE CURVE (AUC)

• Gives extent of absorption• Peak plasma conc. (C

max)• Time to attain peak

conc. (T max) • C max & T max –

indicate rate of Abs

DISTRIBUTION Volume of distribution

Patient Factors (Perfusion, physiological barriers, diseased states, age & gender)

Drug Factors (Plasma protein binding, Tissue affinity, PH & Ionisation, Lipid solubility / redistribution, Structure - activity relationship)

VOLUME OF DISTRIBUTION-Vd• Apparent volume necessary to contain amount

of drug homogenously at the same conc. found in plasma • Vd= Qty of drug administered / concentration

of drug• Lipid insoluble / highly protein bound drug–

restricted to vascular compartment – low Vd• Drugs sequestered in other tissues – large Vd

Vd MODELSOne compartment model

• Body is single/homogenous

Two compartment model

• Differential concentration among various organ systems

ORGAN PERFUSION RATE

• 2 compartments:

• ‘Central’: plasma and highly

perfused tissue reservoirs

• Heart, brain, liver, kidney

• ‘Final’: slowly perfused organs

• Muscle, skin, fat, bone

PHYSIOLOGICAL BARRIERS TO DRUG DISTRIBUTION (1/2)

• Blood brain barrierEndothelial cells tightly joinedSurrounded by less permeable glial cells Lipid soluble & nonionised drugs can enterEg: L-dopa crosses BBB while dopa does not

PHYSIOLOGICAL BARRIERS TO DRUG DISTRIBUTION

(2/2)• Placental Barrier

Allows lipid soluble non polar passive diffusion . High molecular weight dextran & Insulin cannot

cross

DISEASED STATES & SPECIAL SITUATIONS

• Oedema – more fluid in trans-cellular compartment• Sepsis – altered permeability to drugs following

infection/inflammation of bio-membrane• Pregnancy – added tissue and fluid volume (↑Vd)

but ↓albumin – free drug conc. Unaltered: no dose change• Obesity – excessive adipose tissue, ↑Vd for

lipophilic drugs like Diazepam

AGE & GENDER• Total-body water differs with age and sex • TBW of neonates ≈ 75–80% of body weight;

Adult males 60%, Females 55%• Body fat content• Low in children and men; ↓ Vd of lipophilic

drugs • Albumin is ↓ in new born & elderly; ↑ conc. of

unbound drug that primarily bind to albumin

PLASMA PROTEIN BINDING• Reversible binding - circulating drug reservoir• Dynamic equilibrium: Free drug + Protein ↔ Drug-protein

complex• Not accessible to capillary diffusion, metabolism or

excretion• Extensive Protein binding – prolongs duration of action &

availability, but need for larger dosing• Albumin (warfarin, BZD), α1 Acid glycoprotein (quinidine,

CPZ), transcortin (glucocorticoids), Nucleoproteins (digoxin), α globulins (thyroxine), ϒ globulins (antigens)

TISSUE AFFINITY - OTHER RESERVOIRS (1/2)

• Tissues Iodine in thyroidChloroquine in retina (nucleoproteins)CPZ in retinal pigment melaninIsoniacid in Brain

• Muscles Digoxin in heart & skeletal muscles• Connective tissue

Griseofulvin in keratin precursor cells

TISSUE AFFINITY - OTHER RESERVOIRS (2/2)

• Transcellular Chloramphenicol in aqueous humorAminosugars in CSFAmpicillin in endolymph & joint fluidImipramine in pleural fluid

• Fat Thiopentone, phenoxybenzamine

• Bones, teeth & NailsTetracyclines, cisplatin

PH & IONISATION• Weak bases / acids – unionised in basic / acidic PH

respectively • Unionised form crosses Bio-membranes• Plasma PH is basic - Basic drugs unionised; diffuses

into cell - large Vd• But ICF is acidic - larger fraction is ionized &

trapped intracellular

REDISTRIBUTION (LIPID SOLUBILITY)

• Highly lipid soluble drugs get redistributed. • First dose - short acting• Repeated doses - long

acting as drug saturates

In snake bite, recurrent venom effect appear after initial stabilisation; Infusion of 5 ASV vials over 18 hours prevents this. Principle: ASV prevents redistribution of snake venom from bite site Monzavi SM, Dadpour B & Afshari R. Snakebite management in Iran: Devising a protocol. J Res Med Sci. 2014 Feb; 19(2): 153–163.

STRUCTURE ACTIVITY RELATIONSHIP

• Modifications in structure – profound effect on PK• Phenytoin Fosphenytoin (addition of

phosphate at N3 position) – better solubility in IV

• Fluoroquinolones - position 8 substituted with aryl cation – affinity to hypoxic cancer cells*

*Peruccaa P, Savioa M, Cazzalinia O et al. Structure–activity relationship and role of oxygen in the potential antitumour activity of fluoroquinolones in human epithelial cancer cellsJ photochem Photobiol B 2014 Nov;140:57-68

METABOLISM

Pathways Consequences Internal Factors

determining metabolism External Factors

PATHWAYS OF DRUG MTABOLISM

• Phase I reactions• Oxidation, reduction,

hydroxylation

• Mostly microsomal involving CYP enzymes• Results in

active/inactive metabolite

• Phase II reactions• Conjugation reactions

(Glucuronide, N-acetyl, sulfate, amino acid, methyl, glutathione, ribosides)• Mostly non-microsomal

except Glucuronidation• Mostly inactive

metabolites except Morphine glucuronide

HOFMANN ELIMINATION• Inactivation of the drug by molecular

rearrangement • Spontaneous – no Enzymes• Eg: Atracurium

CONSEQUENCES OF METABOLISM

• Formation of inactive metabolitePentobarbitone to Hydroxypentobarbitone

• Formation of active metabolite from inactive drug (prodrug)

Levodopa to dopamineTalampicillin to Ampicillin

• Formation of active metabolite from equally active metabolite

Amitriptyline to NortriptylineCodeine to Morphine

DETERMINANTS OF DRUG METABOLISM (1/2)

INTERNAL FACTORS• Age

Neonates have low microsomal enzymes. Eg: Chloramphenicol causing Grey baby syndrome

Elderly have reduced hepatic flow

• RaceChinese have high alcohol dehydrogenase, low Ald

dehydrogenase

• Genetic variationSlow and fast acetylators of INH (Autosomal Recessive)Atypical pseudocholinesterase for SCh (Autosomal

Recessive)

DETERMINANTS OF DRUG METABOLISM (2/2)

EXTERNAL FACTORS• Environment - Disease

Liver diseases, Cardiac diseases ( blood flow to liver) & Hypothyroidism ( metabolism)

• Nutrition and DietHigh proteins and poor carbohydrates – enhances

metabolismStarvation – inhibits microsomal enzymes

• Drug-drug interaction (by stimulating/inhibiting SER development)

Enzyme inducers – rifampicin, anticonvulsantsEnzyme inhibitors – Valproate, cimetidine, erythromycin

ELIMINATION Clearance & Elimination

kinetics Half Life Routes of elimination Renal Excretion &

determinants Enterohepatic circulation Breast Milk

CLEARANCE (CL)• Volume of biological fluid which is completely cleared

of the drug per unit time• CL of drug by organs is additive

CL= CL renal + CL hepatic + CL other• Kinetics of elimination can follow

First order kinetics (Most drugs)Zero order kinetics (Alcohol)Mixed order kinetics (Phenytoin, tolbutamide,

warfarin, digoxin)

FIRST ORDER KINETICS (1/2)

• Constant fraction of the drug is eliminated at fixed time interval• 100g→50g →25g →12.5g• Clearance remains

constant for a drug at all dosing range• CL = rate of elimination / C

ml/min per Kg• C = conc. Of drug

STEADY STATE CONCENTRATION

• At the 5th half life, 97% of the drug is eliminated.• If a fixed dose of drug is given at the end of every

half life, by 5 t ½ plasma concentration reaches a plateau

ZERO ORDER KINETICS• A constant quantity of drug is

eliminated at fixed time interval• 100g →50g →0g• Clearance decreases with dose

increments• CL = Vm (Km+C)

• vm: maximal rate of elimination(mass/time)• Km: conc. at which half maximal rate

of elimination reached(mass/volume)• C conc. of drug

MIXED ORDER KINETICS• Michaelis – menten Kinetics / saturation kinetics• First order at low doses • Zero order at higher doses• The metabolising enzymes get saturated at higher

concentrations

ELIMINATION CONSTANT (k)

• Fraction of Vd cleared / unit time• Slope of the straight

line obtained by plotting log plasma concentration against time• K = ln2/ t ½ (or) CL/Vd

HALF LIFE (t ½)• The time duration in which the plasma

concentration of the drug falls by 50%• Biological half life is the time duration in which the

pharmacological effect falls by 50%• T1/2 for one compartment model=0.693/K; k –

elimination constant• T1/2 for two compartment model=(0.693*Vss) / CL;

Vss is volume of drug at steady state.

ROUTES OF DRUG ELIMINATION

Alveolar: GA gases, alcohol

Faecal: Purgatives, MgSO4, Streptomycin, bacitracin, neomycin +

bile excreted drugs

Biliary: Quinine, Colchicine, vinblastine, corticosteroids,

erythromycin, CPZ

Renal: Metformin, aminoglycoside etc

Saliva

Hair

Milk

Sweat

Skin

RENAL EXCRETIONa. Glomerular

filtrationb. Active tubular

secretionc. Passive tubular

reabsorption

DETERMINANTS OF RENAL EXCRETION (1/2)

Glomerular filtration• Molecular size - upto 20kD filtered• Protein binding - bound drug cannot be filtered• Renal Blood flowTubular secretion• Drug PH: • Two independent carrier systems for acidic and basic drugs • Competitive inhibition among acidic drugs (Probenecid

inhibits tubular secretion of penicillin/amoxicillin – amox 3g oral + 500mg probenecid in Rx of syphilis*

*Tanizaki R, Nishijima T, Aoki T et al .Clin Infect Dis. (2015) doi: 10.1093/cid/civ270

DETERMINANTS OF RENAL EXCRETION (2/2)

Tubular reabsorption• Lipid solubility- • Quaternary ammonium salts and aminoglycosides are

highly polar and are not reabsorbed

• Ionisation constant (pKa) & PH of urine• Urine is acidic – weak acids are non-ionised and

reabsorbed; vice-versa for weak bases (alkalinisation of urine – reabsorption of weak bases like Morphine)• Strong acids and bases are ionised at all PH and are not

reabsorbed

Diseased states Chronic Renal Failure

DOSING ADJUSTMENT IN RENAL FAILURE

• RF affects at all 3 stages of renal excretion• Also affects• Renal metabolism & bioactivation• Volume of distribution• Non – renal clearance• Protein binding

• Dosing adjustment based on creatinine clearance Cockcroft-Gault equation

BILIARY EXCRETION/ENTEROHEPATIC CIRCULATION

• Enterohepatic circulation prolongs drug action by• Activation of

prodrug (digitoxin)• Reverses

inactivation of inactivated metabolite of active drug (glucoronides)

BREAST MILK EXCRETION• Unwanted

pharmacological action on a nursing infant• Depends on PH

partition principle • Bases are generally

avoided – morphine, chloramphenicol, tetracyclines, OCP

SUMMARY (1/2)S.NO PK Parameter Factors affecting1 Absorption

(Bioavailability)

•Drug related: concentration, dosage forms, lipid solubility, particle size, salt / crystal form, water of hydration. •Patient related: GI contents, transit time, disease states, first pass metabolism, route, area & vascularity

2 Distribution (Volume of distribution)

•Patient Factors: Organ perfusion rate, Physiological barriers, Disease states, Age & Gender •Drug Factors: Plasma protein binding, Tissue affinity, PH & Lipid solubility

SUMMARY (2/2)S.NO PK Parameter Factors affecting

3 Metabolism •Internal Factors: Age, Race, Genetics•External factors: diet, drug intake (induction/inhibition of microsomal enzymes) and diseased states

4 Elimination (Clearance & T ½)

•Glomerular factors: Molecular size, Protein binding/ unbound fraction & Blood flow to kidney•Tubular factors: Urinary PH & ionization constant, Drug PH & lipid solubility• Disease states: renal failure

REFERENCES• Goodman L, Gilman A. Pharmacological basis of

therapeutics. 12th ed. Tata McGraw-Hill; 2012. p. 17-40• Rang HP, Dale MM, Ritter JM, Flower RJ. Pharmacology. 6th

ed. P. 98-130• Sharma HL, Sharma KK. Principles of Pharmacology. 1st ed.

Paras; 2007. p. 27-60• Tripathi KD. Essentials of Medical Pharmacology. 7th ed.

Jaypee; 2013. p. 10-36• Katzung BG, Masters SB, Trevor AJ. Basic & Clinical

Pharmacology. 12th ed. Tata McGraw-Hill; 2012. p. 37-68• Journal articles as mentioned in each slide

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