STUDY OF PRODRUGS IN

PROBLEM RELATED TO

BIOAVAILABILITY AND

ELEGANCE OF FORMULATION

Presented by:-

Mankaran Singh

M.Pharmacy

CT Institute of Pharmaceutical Sciences

Punjab, India1

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.

2

Principle of prodrug Approach

PRO DRUG

DRUG

PRO DRUG

PROMOIETY DRUG

ENZYMES

3

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

4

Classification of ProdrugsCarrier-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).

5

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

6

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

7

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.

8

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, hydrocortisone etc.

Dexamethasone disodium phosphate

water soluble phosphate of Dexamethasone Prodrug of Dexamethasone

9

10

11

2. Organoleptic properties

Unpleasant tastes and odors can be improved by

using prodrug concept

Example: Chloramphenicol

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

12

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

13

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.

14

B. Pharmacokinetic barriers

1. Increasing bioavailabilityMany 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

15

16

a. Preventing first pass metabolism

•Prodrugs may protect a drug from 1st-pass effects.

•Propranolol (antihypertensive drug) suffers from first-

pass 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.

17

b. Intestinal absorption

Eg: Sulindac ( NSAID) its bioavailability is increased

due to increased solubility in GI track.

c. Buccal absorption

Eg: Phenolic compound of ketobemidone increased

lipophilicity of drug.

d. Dermal transport

Eg : Morphine ester have more than 2000folds higher

dermal absorption than morphine

18

e. Rectal absorption

Eh : Bacampicillin a prodrug of ampicilin have more

rectal absorption( 40% more).

f. Ocular absorption

Eg. Dipivefrin a prodrug of adrenaline have more

ocular absorption.

19

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

OH

OH

NH2

CO2H

OH

OH

NH2

Decarboxylase

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

20

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.

21

Targeted Prodrug design represents a strategy for

directed and efficient drug delivery

Site activated prodrugs

Site directed prodrugs

For example:- tumor cells posses higher

concentrations of phosphatases and amidases than

normal cells. Diethylstilbestrol diphosphate was

designed for such site-specific delivery of

diethylstilbestrol in the treatment of breast cancer

22

• A common strategy for slow release is to include a long-

chain 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.

23

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

24

THANK

YOU

25