Prodrugs

STUDY OF PRODRUGS IN PROBLEM RELATED TO BIOAVAILABILITY AND ELEGANCE OF FORMULATION
Presented by:Mankaran Singh, Dinesh Kumar, Deepak Sharma, Gurmeet Singh M.Pharmacy PHARMACEUTICS CT Institute of Pharmaceutical sciences Jalandhar, INDIA AICTE , PCI approved
Introduction
What is a prodrug ? The term prodrug refers to a pharmacologically inactive compound that is converted to an active drug by a metabolic biotransformation. Prodrug is formed by linking drug to an inert chemical by covalent bond which is broken down in vivo to release drug. The biotransformation of a prodrug may occur prior, during, and after absorption, or at specific target sites within the body.
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Principle of prodrug Approach
DRUG
PRO MOIETY
DRUG
ENZYMES
PRO
DRUG
PRO
DRUG
Prodrug design may be useful in circumventing problems associated with:

Solubility Absorption and distribution Site specificity (Diethylstilbestrol diphosphate ) Instability (hemisuccinate ester of propanolol) Prolonged release(Haloperidol decanoate)(cns depressant) Toxicity (aspirin) Poor patient acceptability Formulation problems
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Classification of Prodrugs
Carrier-linked prodrug: contain a group that can be easily removed enzymatically (such as an ester) to reveal the true drug. Ideally, the group removed is pharmacologically inactive and nontoxic while the connecting bond must be labile for efficient activation in vivo. Bioprecursors: Metabolized into a new compound that may itself be active or further metabolized to an active metabolite (e.g. amine to aldehyde to carboxylic acid).
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Carrier-linked prodrugs can be further subdivided into: 1. Bipartate: Composed of one carrier (group) attached to the drug. 2. Tripartate: Carrier group is attached via linker to drug 3. Mutual prodrugs: Two drugs linked together
Steps in Prodrug Design
Identification of drug delivery problem

Identification of desired physicochemical properties Selection of transport moiety which will give prodrug desired transport properties be readily cleaved in the desired biological compartment
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Rationale in prodrug formation

The process of drug development occur in 3 phases:1.Pharmaceutical a. Physical properties like odour,taste etc b. Physiochemical properties (hydrophilicity etc) 2. Pharmacokinetic ( ADME of drug) 3. Pharmacodynamic Drug receptor interaction and is not usually not a phase in which prodrug play a major role.
A. Pharmaceutical barriers
1. Drug Solubility
Formulation of insoluble compounds may be improved by the use of phosphate or hemisuccinate prodrugs Examples: Insoluble glucocorticoids such as dexamethasone, prednisolone, betamethasone,hydrocartisone etc.
Dexamethasone disodium phosphate water soluble phosphate of Dexamethasone

Prodrug of Dexamethasone
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2. Organoleptic properties
Unpleasant tastes and odors can be improved by using prodrug concept Example: Chloramphenicol
Chloramphenicol
OH OH Cl Cl O O-Na+ O O O H N O H O Cl Cl
H N O
Esterase
O2N
O2N
or Water
OH O-Na+ O
Chloramphenicol Succinate
Sodium succinate
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3. Drug stability Breakdown or degradation of active drugs on prolonged storage Common problem of oral drugs which are unstable in gastric acid 5-Aminosalicylic acid (mesalazine) ;
Treatment of ulcerative colitis Unstable in gastric acid in stomach Site of action is ileum/colon
Eg : Hetacillin a prodrug of Ampicillin which is stable in aq solution

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4. Reduction of pain at site of injection Pain at site of injection is related to various factors like viscosity, pH, isotonicity, precipitation at site of injection etc. Clindamycin hydrochloride produces pain at site of action due to precipitation of free clindamycin but its prodrug Clindamycin phosphate which is higher soluble produces no irritation at site of injection.
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B. Pharmacokinetic barriers 1. Increasing bioavailability Many drugs are poorly or unpredictably absorbed from gastrointestinal tract Prodrug design has been utilized in a number of cases to optimize the absorption of such drugs thereby improving their bioavailability Example: Ampicillin is used as their lipophilic esters like pivampicillin & bacampicillin to improve drug absorption Ampicillin R=H
Pivampicillin R= CH2-O-CO-C(CH3)3 Bacampicillin R= CH(CH3)-O-COOC2H5
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a. Preventing first pass metabolism Prodrugs may protect a drug from 1st-pass effects. Propranolol (antihypertensive drug) suffers from firstpass elimination resulting in decreased bioavailability of oral doses compared to i.v. injections. One of the major metabolites is the O-glucuronide. The hemisuccinate ester was designed to block glucuronide formation resulting in an 8-fold increase of plasma levels of propranolol.
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2. Drug distribution The modification of a drug to a prodrug may lead to enhanced efficacy for the drug by differential distribution of the prodrug in body tissues before the release of the active form. Example: L-dopa is formulated as prodrug of dopamine to enhance the dopamine level in the brain tissues
HO HO CO2H NH2 HO
Decarboxylase
HO
NH2
Dopamine
Brain has a specific transport system for L-amino acids
Dopamine does not cross the blood brain barrier efficiently, is rapidly metabolized by oxidative deamination, and can cause peripheral side effects
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C. Other application of prodrugs 1. Reduction in Toxicity The prodrug that is converted to the active drug at the target site itself greatly reduced side effects of highly toxic drugs. Derivative of salicylic acids are one of the oldest example that are characterized by lesser toxicity than their parent drugs. Salicylic acid is a good pain-killer but causes gastric irritation and bleeding because of carboxyl group. It accumulates in the gastric mucosal cells. Aspirin, esters of salicylic acid, suppresses gastric irritation.
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Targeted Prodrug design represents a strategy for directed and efficient drug delivery Targeting the prodrug to a specific enzyme Targeting the prodrug to a specific membrane transporter For example:- tumor cells posses higher concentrations of phosphatases and amidases than normal cells. Diethylstilbestrol diphosphate was designed for such site-specific delivery of deithylstilbestrol in the treatment of breast cancer
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A common strategy for slow release is to include a longchain aliphatic ester to slow hydrolysis. It is particularly useful for the treatment of psychoses where patients require medication for extended periods and patient compliance is low.
EG: Haloperidol: potent orally active CNS depressant, sedative, tranquilizer. peak plasma levels between 2-6 hr after administration Haloperidol decanoate: injected i.m. as a solution in sesame oil Antipsychotic activity lasts ~ 1 month.
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CONCLUSION Prodrugs are used to overcome several undesirable properties in order to achieve the best clinical drug application Site specificity is central to the prodrug development strategy
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THANK YOU
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STUDY OF PRODRUGS IN PROBLEM RELATED TO BIOAVAILABILITY AND ELEGANCE OF FORMULATION

Principle of prodrug Approach

Prodrug design may be useful in circumventing problems associated with:

Steps in Prodrug Design

Identification of drug delivery problem

Rationale in prodrug formation

Dexamethasone disodium phosphate water soluble phosphate of Dexamethasone

Eg : Hetacillin a prodrug of Ampicillin which is stable in aq solution

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