Presenter : Ms. Jyotsna G. Patil

M.Pharmacy (Quality Assurance) 1st semester

Guided by: Mrs. Malathi Raghunath

GAHLOT INSTITUTE OF PHARMACY

What arePRODRUGS

The term ‘Prodrug’ describes compounds whichundergo biotransformation prior to exhibitingtheir pharmacological effects.

Prodrugs are pharmacologically inactive chemical derivatives of a drugmolecule that require a transformation (enzymatic or nonenzymatic)within the body in order to release the active drug.

Goal: improve ADME/Tox- or physicochemical properties

Prodrug is successfully studied to target the drug specifically to siteof action for better therapy.

An illustration of the prodrug concept (Huttunen et al., 2011)

Objectives of prodrug design Pharmaceutical objective

- improved solubility (chloramphenicol succinate ester)

- improved chemical stability (propranolol hemisuccinate ester)

- improved taste, odour (clindamycin palmitate)

- decreased irritation & pain (sulindac, clindamycin phosphate)

pharmacokinetic objectives

- improved absorption (carbecillin, geocillin)

- decreased presystemic metabolism (acetonide of triamcinolone)

- improved absorption by non-oral routes (amino acid ester approach)

- improved prolong duration of action (fluphenazine ester prodrugs)

pharmacodynamic objectives

- masking of reactive agent to improve its therapeutic index

- in situ activation of a cytotoxic agent (tirapazamine)

ADME ADME is an abbreviation in pharmacokinetics and

pharmacology for “ Absorption, Distribution, Metabolism and Excretion.”

It describes the disposition of pharmaceutical compound within an organism.

Absorption (bioavailability)

Distribution (lower plasma concentration)

Metabolism (metabolites- active/inactive)

Excretion (termination of drug’s action)

Problems associated with ADME

Incomplete absorption

Too rapid or too slow transport of the drugs to the body

Incomplete systemic delivery of an agent

Toxicity problems

Poor site specificity

USE OF PRODRUGS TO OVERCOME PHARMACOKINETIC BARRIERS

ABSORPTION PROBLEMS

Poor absorption due to:

1. High water solubility

2. Limited water solubility eg. cardiac glycoside such as gitoxin.

Enhancement of Oral Absorption Drug To improve absorption

Water soluble

vitamins

derivatization of thiolate ion to form lipid

soluble prodrugs

dopamine L-Dopa (active transport mechanism)

ampicillin acyloxymethyl ester (bacampicillin,

talampicillin and pivampicillin

carbenicillin α-carboxy ester (carbecillin, geocillin)

Gitoxin

(water insoluble)

penta acetyl prodrug

Prodrugs used in enhanced oral absorption

ampicill in8.44

O

N

NH2

NH

O

S

COO-

esterase

bacampicillin (R = CH3, R' = OEt)

pivampicillin (R = H, R' = t-Bu)

8.45

8.46

..

+ R'COOH

whenR' = OEt

EtOH

+ CO2

8.44

NH2

N

SNH

O

Ph

O

OO O

R

R'

O

NH2

N

SNH

O

Ph

O

OO

R

R H

O

OH

1)Ampicillin prodrugs

2)Dopamine prodrug

Dopamine is water soluble

Levodopa is rapidly absorbed from the small intestine.

Enhancement of Ophthalmic Absorption The usefulness of epinephrine as adrenergic agent in

the treatment of glaucoma is limited due to its highlypolar nature.

Dipivalyl derivative of epinephrine formed by theacylation of phenolic hydroxyl groups showedenhanced therapeutic effectiveness.

Lipid solubility of Dipivalyl derivatives is far superiorto its parent compound, which facilitates its transportthrough a lipoidal barrier during corneal absorption.

Dipivalyl Epinephrine: A New Pro-Drug in theTreatment of Glaucoma

Enhancement of Percutaneous Absorption Mefenide and corticosteroid

The problem of poor percutaneous absorption of corticosteroid was overcome by making various ester prodrugs.

Mefenide and corticosteroid are used in the treatment of inflammatory, burn therapy, allergic and pruritic conditions, but have limited application due to poor percutaneous absorption.

Prevention of pre-systemic metabolism Presystemic metabolism of drug is due to

- Phenolic moiety

- Oxidative N– and O– dealkylation

- Ester cleavage

- Peptide degradation

Two types of drug

- rapidly degraded by the acid condition of the stomach

- degrade due to enzymes present in the gastrointestinal mucosa and liver

Prevention of pre-systemic metabolism

The first pass metabolism of a drug can be prevented ifthe functional group susceptible to metabolism isprotected temporarily by derivatization.

The prodrug approach was successfully used toovercome the problem of considerable metabolism ofsteroid drugs, propranolol, dopamine, morphine andcatecholamines

Prevention of pre-systemic metabolismDRUG PRODRUG APPROACH

Steroids Acetylated derivatives

Corticosteroids 17 α, 21-acetonides

Propranolol Hemisuccinate ester

Dopamine L-Dopa

Morphine Diacetyl prodrug

Morphine prodrug Morphine is subject to extensive first-pass metabolism (a

large proportion is broken down in the liver), so, if taken orally, only 40–50% of the dose reaches the central nervous system.

When someone takes heroin, either by means of injection, smoking, the drug enters the bloodstream, then travels towards the brain, hits the blood-brain barrier, already having been converted to 6-mono-acetylmorphine (6MAM) through hydrolysis. This compound, unlike pure morphine, is lipid-soluble and races through into the brain with almost no delay. Then the 6MAM rapidly breaks down into morphine.

Morphine prodrug

Morphine Heroin

Corticosteroid prodrug Several corticosteroids undergo extensive first-pass

hepatic metabolism which can be prevented by use of their ester or ether prodrugs.

Longer duration of action Prolongation of duration of action of a drug can be

accomplished by the prodrug approach and can take two forms.

First the input of drug in to the body can be controlled by a prodrug/drug delivery formulation complex, which by design releases drug at a controlled rate at the absorption site, followed by conversion to drug prior to or just after absorption.

Second a prodrug can be designed wherein the conversion to the parent drug becomes the release rate limiting factor in the systemic milieu.

This approach is most useful in case of neuroleptic drugs to avoid large fluctuation in plasma levels.

This could be successfully achieved by administering heptanoate and decanoate esters of fluphenazine in sterile sesame oil.

Fluphenazine prodrug

Fluphenazine is a short acting piperazine phenothiazine.

Onset of action: within 1 hr.

Duration of action: 6 to 8 hr.

Reported half life: 13 to 33 hr. or more

Cont...

Fluphenazine esters in sesame oil slows their release resulting in longer duration of action.

Onset of action: 24 to 72 hr.

Avg. duration of action: 2 to 3 weeks.

To Diminish Local and Systemic Toxicity of Drugs

Therapeutic activity without toxicity

Very difficult unless site specific delivery of drug is achieved

Various non steroidal anti inflammatory drugs like salicylic acid and indomethacin severely damage the GI mucosa due to presence of free carboxylic group.

Cont…

Few other therapeutic agents such as sulindac sulfide, 5, 5-ethyl phenylhydrazine and phenytoin, and antibiotic such as adriamycin suffer with the problem of toxicity due to inadequate aqueous solubility, improper distribution and high tissue distribution respectively