This document discusses the concept and objectives of prodrugs. It defines prodrugs as biologically inert derivatives of drug molecules that undergo enzymatic or chemical conversion in the body to release the active drug. The key objectives of prodrug design are to improve pharmaceutical and pharmacokinetic properties like solubility, stability, absorption and to decrease toxicity. Examples of different types of prodrugs and their applications like masking taste, reducing irritation and enhancing bioavailability are provided.

1. CONCEPT OF PRODRUGS
Prepared by…….
Abhijit N. Daf
M-pharm Pharmaceutical Chemistry

2. DEFINITION
 The term prodrug, introduced in 1958 by
Adrein albert,
“ Biologically inert derivatives of drug molecules
that undergo an enzymatic and/or chemical
conversion in vivo to release the
pharmacologically active parent drug”
 A prodrug is a chemically modified inert
drug precursor, Which upon
biotransformation liberates the
pharmacologically active parents
compound.

3. OBJECTIVES OF PRODRUG DESIGN
 There are three basic, overlapping
objectives in prodrug research
1. Pharmaceutical objective
 To improve solubility, Chemical stability
 To decrease irritation and/or pain after
local administration.
 To reduce problems related with the
pharmaceutical technology of the agent.

4. CON…
2. Pharmacokinetic objectives
 To improve absorption {oral & Non oral routes}
 To decrease presystemic metabolism to improve
time profile.
 To increase organ or tissue-selective delivery of
the active agent.
3. Pharmacodynamic objective
 To decrease toxicity and improve therapeutic
index.
 To design single chemical entities combining two
drugs (co-drugs strategy)

5. EXAMPLES OF PRODRUG

6. CLASSIFICATION OF PRODRUG
Prodrugs
Carrier linked
prodrugs
Bipartite
prodrugs
Tripartite
prodrugs
Mutual
prodrugs
Biprecursor
Prodrugs
Polymeric
prodrugs

7. 1. CARRIER LINKED PRODRUGS
 Carrier linked prodrug consist of the attachment of a
carrier to the active drug to alter its physicochemical
properties.
 The subsequent enzymatic or non-enzymatic
mechanism release the active drug moiety

8. A. BIPARTITE PRODRUG
 It composed of one carrier group attached to the drugs.
 Such prodrugs have greatly modified lipophilicity due to the
attached carrier.
 The active drug is released by hydrophilic cleavage either
chemically.

10. B. TRIPARTITE PRODRUGS
Drug
Linking
structure Carrier
THE CARRIER GROUPS IS ATTACHED VIA LINKER/SPACER TO DRUGS

11. C. MUTUAL PRODRUGS
 A mutual prodrug consist of two pharmacologically active
agents coupled together so that each as a promoiety for
the other agent and vice versa.

12. 2. BIOPRECURSORS
 The biprecursor does not contain a carrier & temporary
linkage between the active drug & carrier moiety, but
designed contains a latent functional group that is
metabolically or chemically transformed into active drug.
 Eg: Phenylbutazone, gets metabolized to oxyphenbutazone
that is responsible for the anti-inflammatory activity of the
parent drug.
3. POLYMERIC PRODRUGS
o Also known as macromolecular prodrug, the drug is
dispersed or incorporated into the polymer ( both
naturally occurring & synthetically prepared) system
without formation of covalent bond between drug &
polymer.

13. NOVEL CLASSIFICATION
 Type I Prodrugs
 Type II Prodrugs
 Type-I: Prodrugs are bioactivated inside the cells
(Intracellularly). Examples of these are anti-viral
nucleoside analogs that must be phosphorylated & the
lipid-lowering statins.
 Type-II: Prodrugs are bioactivated outside the cells
( Extracellularly ), especially in digestive fluids or in the
body’s circular system.

14. APPLICATION OF PRODRUGS
 Pharmaceutical application
Masking taste & odour
 Undesirable taste arises due to adequate solubility &
interaction of drug with taste receptor.
Reduction of gastric irritation
 Eg: Aspirin is a prodrug of salicylic acid designed to
reduce gastric irritation.

15.  REDUCTION IN PAIN AT SITE OF INJECTION
 Pain caused by intramuscular injection is mainly due to
the weakly acidic nature or poor aqueous solubility of
drugs.
 Eg: IM injection of antibiotics like clindamycin &
anticonvulsant like phenytoin was found to be painful due
to poor solubility, so prodrugs are produce like
2’phosphate ester of clindamycin and hydantoic ester
prodrug of phenytoin fosphenytion an aqueous soluble
form of phenytoin respectively.

16.  ENHANCEMENT OF CHEMICAL STABILITY
 Chemical stability is an outmost necessary parameter for
every therapeutic agent.
 The prodrug approach is based on the modification of the
functional group responsible for the instability or by
changing the physical properties of the drug resulting in
the reduction of contact between the drug and the media
in which it is unstable.
 PHARMACOKINETIC APPLICATIONS
 Enhancement of bioavailability/Enhancement of oral
bioavailability
o Absorption of water soluble vitamin was enhanced by
derivatization of thiolate ion to form lipid soluble prodrugs.

17.  Enhancement of ophthalmic bioavailability
 Enhancement of precutaneous bioavailability
 Enhancement of topical administration
 Prevention of presystemic metabolism
Oral administration, a drug must pass through two
metabolizing organs i.e, Liver and gastrointestinal mucosa,
before reaching the general circulation
Prodrugs may protect a drug from presystemic metabolism.

18. PROLONGATION OF DURATION OF ACTION
 Prodrugs are designed to be slowly converted to
the active drug to prolong or sustain a drugs
activity.
 Reduction local and systemic toxicity of drugs
o An important objective of drug design is to develop
a moiety with high activity & low toxicity.