Presentation on

Antibiotics used as prodrugs

Prepared for

Mr. Apurba Sarker Apu

Senior Lecturer

Dept. of Pharmacy

East West University

Prepared by

Tamanna Rahman ID: 2008-1-70-052

Tahmina Khanom ID: 2005-2-70-006

Abhijit das ID: 2007-1-70-052

Farzana Rahman ID: 2007-1-70-047

Anisur rahman ID: 2006-2-70-108

What is a Prodrug?A prodrug is an inactive derivative that will

be converted to the active drug in vivo.

Prodrugs are used when drugs have unattractive physicochemical properties.

Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation

 

Why prodrugs are designed

If the drugs have the following properties:

•Physical Properties

Poor aqueous solubilityLow lipophilicityChemical instability

•Pharmacokinetic Properties

Poor distribution across biological membranesGood substrate for first-pass metabolismRapid absorption/excretion when long-term effect DesiredNot site-specific

Why antibiotics are used as prodrug

Antibiotics constitute a valuable adjunct to the physicians therapeutic effects in the battle against a wide variety of infectious diseases. While many antibiotics can be utilized with a minimum of modification to ensure their therapeutic effect, exceptions exist where extensive development must be undertaken prior to their becoming efficacious medicinal agents.

Certain shortcomings of these agents, such as lack of stability or poor bioavailability, can be minimized or eliminated by the use of carefully designed dosage formulations. In many instances, however, formulation development fails to improve those properties of the antibiotic that are necessary to ensure therapeutic efficacy. It is in this area that chemical modification (prodrug formation) of the parent antibiotic molecule plays an important role.

There are certain drugs that are used as prodrugs.

Such as- Ampicillin

Cephalosporins

Carbapenem

Chloramphenicol

Ampicillin

Beta Lactum Antibiotic

Poorly absorbed (30% absorbed)

Show the form of ampicillin that will be observed in the intestine (pH ~8).

Scientists suggest prodrug forms of ampicillin that might be better absorbed after oral dosing.

Ampicillin prodrugs have been designed by modifying the “R” group in ampicillin structure

• Objective- to increase lipophilicity.A number of ampicillin prodrugs have

been synthesized to enhance its oral bioavailability.

Such as- PivampicillinTalampicillinBacampicillin

Hetacillin

Breakdown of pivampicillin within the biologic system

Comparative study between pivampicllin & ampicillin

The absorption and excretion of equivalent doses (500 mg) of ampicillin, pivampicillin, and amoxycillin were compared in 10 healthy volunteers

Comparative study between pivampicllin & ampicillin (Cont.)

Empty Stomach

given with breakfast

Their Mean Half Life was nearly the same

But a significant difference was found in their mean serum level and cumulative excretion data.

60.9 min for ampicillin

58.4 min for pivampicillin

62.2 min for amoxycillin.

Mean serum level comparison

Cumulative renal excretion data

By these criteria, pivampicillin was the best-absorbed drug, with absorption-

3.0 to 3.6 times higher than that of ampicillin

1.2 to 1.5 times higher than that of amoxycillin,

CarbapenemCarbapenems are the most potent class of β-

lactam antibiotics, which have a broad spectrum of potent antibacterial activities against Gram-positive and Gram-negative organisms, including P. aeruginosa.

Carbapenems are stable to hydrolysis by various β-lactamase, and thus, effective against most cephalosporin-resistant microorganisms.

Imipenem, panipenem and meropenem (MEPM) have long been used for serious infectious diseases, including complicated urinary tract infection and complicated respiratory tract infection.

Imipenem and panipenem are unstable chemically and to renal dehydropeptidase-I,

thus used in combination with cilastatin for Imipenem and betamipron for panipenem.

MEPM and doripenem have a 1β-methyl group, and are stable against chemical degradation and hydrolysis by dehydropeptidase-I and are thus used without cilastatin or betamipron.

Carbapenem

Imipenem+

cilastatin

Panipenem+

betamipron

Meropenem

(1β-methyl group)

Meropenem Meropenem is an ultra-broad

spectrum injectable antibiotic used to treat a wide variety of infections, including meningitis and pneumonia. It is a beta-lactam and belongs to the subgroup of carbapenem.

It is marketed outside Japan by AstraZeneca with the brand names Merrem and Meronem. It gained US FDA approval in July 1996. It penetrates well into many tissues and body fluids including the cerebrospinal fluid, bile, heart valves, lung, and peritoneal fluid.

Tructure activity RelationshipAll these parenteral carbapenems have a carboxyl group at the carbapene C-3 position, which is essential for interaction with a target protein, penicillin-binding protein

A basic group at the pyrrolidine N-1 position, which promote their invasion through D2 porin into P. aeruginosa, resulting in little oral absorption because of the two ionizable groups. Many attempts to find new orally active carbapenems have been reported, in which the basic group at the pyrrolidine N-1 position was eliminated and the carboxyl group was esterified by easily hydrolizable promoiety to increase oral absorption, but most showed very weak antibacterial activity against P. aeruginosa. carbapenem. Tebipenem showed potent activity against penicillin-resistant S. pneumoniae, β-lactamase-negative ampicillin-resistant H. influenzae, H. influenzae and E. coli;

however, unlike MEPM, tebipenem has no activity against β-lactamase-producing P. aeruginosa and its therapeutic use is still limited to pediatric otitis media, rhinitis and pneumonia. In the present study, we attempted to increase the oral bioavailability of MEPM by chemical modification to a double-promoiety prodrug, because MEPM is chemically and biologically more stable than imipenem and panipenem, and has a lower molecular weight than doripenem. Furthermore, its efficacy in infection therapy and safety have been established

Double-promoiety prodrugs of MEPM, in which two kinds of lipophilic promoieties were introduced at the carbapene C-3 and pyrrolidine N-1 position of MEPM to increase oral bioavailability, were synthesized and biologically evaluated.

Drug designFirst, single-promoiety prodrugs of MEPM

were designed using pivaloyloxymethyl (POM) and 1-ethylpropyloxycarbonyloxymethyl (EPC).

β-Lactam antibiotics, such as penicillins, cephalosporins and carbapenems, have a carboxyl group that decreases their membrane permeability, resulting in low oral absorption. In many orally used penicillins and cephalosporins, their carboxyl group is esterified with a lipophilic and hydrolyzable promoiety: these prodrugs are efficiently absorbed and then rapidly hydrolyzed to an active form.

Second, double-promoiety prodrugs of MEPM were designed by introduction of the second lipophilic promoiety to the pyrrolidine N-1 position of MEPM because no single-promoiety prodrugs of parenteral carbapenems have been successfully developed, probably due to their basic side chain, which is also considered to decrease their membrane permeability. As the second lipophilic promoiety, carbonate promoieties (isobutyryloxymethyloxycarbonyl, propionyloxymethyloxycarbonyl, butyryloxymethyloxycarbonyl and valeryloxymethyloxycarbonyl) were used.

The general synthetic routes of prodrugs of MEPM are shown in All prodrugs were prepared from MEPM.

Single-promoiety prodrugs were prepared by esterification with the corresponding alkyl iodides, and afforded by N-alkylation of pyrrolidine moiety.

Double-promoiety prodrugs were prepared by N-alkylation and esterification.

ResultsPhysicochemical properties and oral absorption of single- and double-promoiety prodrugs of MEPM

The pharmacokinetics of MEPM after oral administration of compounds was reevaluated to more precisely determine the parameters:

Blood was taken at 10, 20, 30, 45, 60, 90 and 120 min after administration.

The Cmax was similar between compounds 4 and 8, and AUC and bioavailability were slightly higher and T1/2 was longer in compound

It was confirmed that oral absorption of MEPM was effectively increased in the double-promoiety prodrugs in comparison with the corresponding single-promoiety prodrugs.

CephalosporinsThe

cephalosporins are a class of β- lactum antibiotic originally derived from Acremonium, which was previously known as Cephalosporium". 

 

CefuroximCefuroxime is a second-

generation cephalosporin antibiotic that has been widely available in the USA as Ceftin since 1977. Cefuroxime, like the penicillins, is a beta-lactam antibiotic. By binding to specific penicillin-binding proteins (PBPs) located inside the bacterial cell wall, it inhibits the third and last stage of bacterial cell wall synthesis.

Cefuroxime-AxetilCefuroxime-Axetil is an ester of

cefuroxime, which can be used as an oral antimicrobial agent. The prodrug is hydrolysed by esterases of the gut mucosa, setting free the active cefuroxime. This second generation cephalosporin is well known since more than a decade as a cephalosporin possessing high stability against gram positive and gram negative beta-lactamases. Due to its pharmacokinetic properties and its wide spectrum of activity, cefuroxime-axetil was recommended to be used as an oral agent in bacterial infections of the respiratory tract.

Why the prodrug form is prefered:

Cephalosporins usually exhibit poor bioavailabilities whenthey are given orally. Higher values are obtained only withcephalosporins that are taken up by carrier systems or whenthe polarity of the carboxylic acid group in the 4 position isreduced by esterification . Esterification of the carboxylicacid group produces derivatives which can be absorbed bypassive diffusion. Therapeutically useful compounds can,

however,be obtained only if the absorbed prodrug ester is readilyconverted back to the active drug. The success of the prodrugester approach depends vitally on the solubility and lipophilicityof the prodrug ester as well as its stability to chemical andenzymatic ester cleavage.

PHARMACOKINETICSAfter oral administration, Cefuroxime Axetil is

absorbed from the gastrointestinal tract and rapidly hydrolyzed by nonspecific esterases in the intestinal mucosa and blood to cefuroxime. Cefuroxime is subsequently distributed throughout the extracellular fluids. The axetil moiety is metabolized to acetaldehyde and acetic acid.

PHARMACOKINETICS

Comparative Analysis

Side Effect There are a number of side effects with cefuroxime axetil that you

should report to your healthcare provider. These include but are not limited to:

  Watery or bloody diarrhea (which can occur even after you have

finished the medication) Seizure Signs of an allergic reaction, such as:  

An unexplained rash Hives Itching Unexplained swelling (especially of the lips, mouth, or throat) Wheezing or other breathing problems.

Side EffectDiarrhea or loose stools -- in up to 10.6

percent of people Nausea and vomiting -- up to 6.8 percent Vaginitis (vaginal inflammation or

infection) -- up to 5.4 percent Dislike of taste (for the oral suspension

form) -- up to 5 percent Diaper rash-- up to 3.4 percent.

Rare Side EffectsThese rare cefuroxime axetil side effects included but were

not limited to:

Abdominal pain (stomach pain) and cramping Gas HeadacheChills Loss of appetite Thirst Mouth sores Indigestion or heartburnDizziness Drowsiness.

Contraindications

Cefuroxime Axetil products are contraindicated in patients with known allergy to the cepha losporin group of antibiotics.

NH

Cl

OO

O-Na+O

O

ClOH

O2N

NH

Cl

OH

O

ClOH

O2N

O-Na+O

O

OH

Esterase

or Water

Chloramphenicol Succinate

Chloramphenicol

Sodium succinate

• Enzymatic and intramolecular spontaneous hydrolysis

• Increased water solubility, ester itself is inactive as an antibiotic

• Promoiety should be nontoxic and easily excreted

• Type of promoiety chosen is a function of properties desired