Prodrugs

1. By
Gunjan Kalyani
M. Pharm. (Pharmaceutical Chemistry)
Mobile: +91-8349204583
Mail ID: kalyani.gunjan@yahoo.in

2. A. Almost all drugs possess some undesirable physicochemical and
biological properties.
B. Drug candidates are often discontinued due to issues of poor
pharmacokinetic properties or high toxicities
C. Their therapeutic efficacy can be improved by eliminating the
undesirable properties while retaining the desirable ones.
D. This can be achieved through biological, physical or chemical means.
A. The Biological approach is to alter the route of administration which
may or may not be acceptable to patient.
B. The Physical approach is to modify the design of dosage form such as
controlled drug delivery of drug.
C. The best approach in enhancing drug selectivity while minimizing
toxicity, is the chemical approach for design of prodrugs.

3. A. The term prodrug, introduced in 1958 by Adrien Albert, relates to
“Biologically inert derivatives of drug molecules that undergo an
enzymatic and/or chemical conversion in vivo to release the
pharmacologically active parent drug.”
B. A prodrug is a chemically modified inert drug precursor, which upon
biotransformation liberates the pharmacologically active parent
compound.
Definition
A. The first compound fulfilling the classical criteria of a prodrug was acetanilide,
introduced into the medical practice by Cahn and Hepp in 1867 as an antipyretic
agent. Acetanilide is hydroxylated to biologically active acetaminophen.
B. Another historical prodrug is Aspirin (acetylsalicylic acid), synthesized in 1897 by
Felix Hoffman (Bayer, Germany), and introduced into medicine by Dreser in 1899.
C. The prodrug concept was intentionally used for the first time by the Parke-Davis
company for modification of chloramphenicol structure in order to improve the
antibiotic’s bitter taste and poor solubility in water. Two prodrug forms of
chloramphenicol were synthesized: chloramphenicol sodium succinate with a good
water solubility, and chloramphenicol palmitate used in the form of suspension in
children.
History of Prodrugs

4. History of Prodrugs

5. A. Improving formulation and administration.
B. Enhancing permeability and absorption.
C. Changing the distribution profile.
D. Protecting from rapid metabolism.
E. Overcoming toxicity problems.
Rationale for prodrug design

6. Properties of Ideal Prodrug

7. There are three basic, overlapping objectives in prodrug research:
A. Pharmaceutical Objectives
B. Pharmacokinetic Objectives
C. Pharmacodynamic Objectives
Objectives of Prodrug Design
A. To improve solubility,
chemical stability, and
organoleptic properties.
B. To decrease irritation
and/or pain after local
administration.
C. To reduce problems
related with the
pharmaceutical
technology of the active
agent.
Pharmaceutical Objectives
A. To improve absorption
(oral and by non-oral
routes).
B. To decrease
presystemic metabolism
to improve time profile.
C. To increase organ/
tissue-selective
delivery of the active
agent.
Pharmacokinetic Objectives Pharmacodynamic Objectives
A. To decrease toxicity
and improve
therapeutic index.
B. To design single
chemical entities
combining two drugs
(co-drugs) strategy.

8. A. The awareness that the onset, intensity and duration of drug action are
greatly affected by the physicochemical properties of drug has promoted
the emergence of various prodrugs.
B. Most of the limitations can be overcame by prodrug approach, but after
overcoming the various barriers, the prodrug should rapidly convert into
active moiety after reaching the target site.
C. The design of an efficient, stable, safe, acceptable and aesthetic way
to target a drug to its site of action while overcoming various physical,
chemical and social barriers is certainly the utilization of the prodrug
approach holds great potential.
Prodrug concept

9. A. Drug latentiation is the chemical modification of a biologically active
compound to form a new compound, which in vivo will liberate the parent
compound.
B. Drug latentiation is synonymous with prodrug design.
Drug latentiation

10. Schematic Illustration of produrg concept
Barrier

11. Classification of Prodrugs

12. A. Carrier linked prodrug consists of the attachment of a carrier group to
the active drug to alter its physicochemical properties.
B. The subsequent enzymatic or non-enzymatic mechanism releases the
active drug moiety.
Carrier linked prodrug

13. A. It is composed of one carrier (group) attached to the drugs.
B. Such prodrugs have greatly modified lipophilicity due to the attached
carrier. The active drug is released by hydrolytic cleavage either
chemically or enzymatically.
C. E.g. Tolmetin-glycine prodrug.
Bipartite prodrug
Glycine Glycine

14. Tripartite prodrug
A. The carrier group is attached via linker/spacer to drug.
B. The parent drug is attached directly to promoiety.
Linking
Structure

15. Mutual Prodrugs
A. A mutual prodrug consists of two pharmacologically active agents
coupled together so that each acts as a promoiety for the other
agent and vice versa.
B. A mutual prodrug is a bipartite or tripartite prodrug in which the
carrier is a synergistic drug with the drug to which it is linked.

16. C. Benorylate is a mutual prodrug aspirin and paracetamol.
D. Sultamicillin, which on hydrolysis by an esterase produces
ampicillin & sulbactum.
Mutual Prodrugs

17. A. Bioprecursor prodrugs produce their effects after in vivo chemical modification of
their inactive form.
B. Bioprecursor prodrugs rely on oxidative or reductive activation reactions unlike the
hydrolytic activation of carrier-linked prodrugs.
C. They metabolized into a new compound that may itself be active or further
metabolized to an active metabolite.
D. The bioprecursor does not contain a temporary linkage between the active drug
and carrier moiety, but designed from a molecular modification of an active
principle itself.
E. Eg: phenylbutazone. Phenylbutazone gets metabolized to oxyphenbutazone that is
responsible for the anti inflammatory activity of the parent drug.
Bioprecursors

18. A. Also known as macromolecular prodrug, the drug is dispersed or
incorporated into the polymer (both naturally occurring and
synthetically prepared) system without formation of covalent bond
between drug and polymer.
B. Eg: p–phenylene diamine mustard is covalently attached to polyamino
polymer backbone polyglutamic acid.
Polymeric Prodrugs
A. Type I Prodrugs
B. Type II Prodrugs
C. Type I prodrugs are bioactivated inside the cells (intracellularly).
Examples of these are anti-viral nucleoside analogs that must be
phosphorylated and the lipid-lowering statins.
D. Type II prodrugs are bioactivated outside cells (extracellularly),
especially in digestive fluids or in the body's circulation system,
Novel Classification

19. Novel Classification
Type Bioactivation
site
Subtype Tissue location
of bioactivation
Examples
Type I Intracellular Type IA Therapeutic
target
tissues/cells
a) Aciclovir,
fluorouracil
b) Cyclophosphamide
c) diethylstilbestrol
diphosphate
d) LDOPA,
e) Mercaptopurine
f) Mitomycin
g) zidovudine
Type IB Metabolic
tissues (liver,
GI, lung,
mucosal cell
etc.)
a) Carbamazepine
b) Captopril
c) Heroin
d) Leflunomide
e) Phenacetin
f) primidone,
g) Psilocybin
h) Sulindac
i) codeine

20. Type Bioactivation
site
Subtype Tissue location
of bioactivation
Examples
Type II Extracellular Type IIA GI fluids a) Loperamide oxide
b) Oxyphenisatin
c) sulfasalazine
Type IIB Systemic
circulation and
other
extracellular
fluid
compartments
a) Acetylsalicylate
b) Bacampicillin
c) Bambuterol
d) chloramphenicol
e) Succinate
f) Dipivefrin
g) Fosphenytoin
h) lisdex
i) Amfetamine
j) pralidoxime
Type IIC Therapeutic
target
tissues/cells
a) ADEPTs
b) GDEPs
c) VDEPs
Novel Classification

21. Marketed Prodrugs

22. A. Formation of unexpected metabolite from the total prodrug
that may be toxic.
B. The inert carrier generated following cleavage of prodrug may
also transform into a toxic metabolite.
C. During its activation stage, the prodrug might consume a vital
cell constituent leading to its depletion.
Limitations of Prodrug Design

23. CONCLUSION
A. Prodrug design is a part of the general drug discovery
process, in which a unique combination of therapeutically
active substances is observed to have desirable
pharmacological effects.
B. In human therapy prodrug designing has given successful
results in overcoming undesirable properties like absorption,
nonspecificity, and poor bioavailability and GI toxicity.
C. Thus, prodrug approach offers a wide range of options in
drug design and delivery for improving the clinical and
therapeutic effectiveness of drug.

24. Acknowledgements
A. D.A.V. Public School, ACC Colony, Jamul – 490024, Durg, Chhattigarh, India (1990 –
2004)
B. University Institute of Pharmacy, Pt. Ravishankar Shukla University, Raipur, Chhattisgarh,
India (2005 – 2009)
C. Shri Rawatpura Sarkar Institute of Pharmacy, Kumhari, Durg, Chhattisgarh, India (2010 –
2012)
D. Royal College of Pharmacy, Raipur, Chhattisgarh, India (March – October 2013)
E. National Center for Natural Resources (NCNR), Pt. Ravishankar Shukla University, Raipur,
Chhattisgarh, India (2013 – 2017)
F. Columbia Institute of Pharmacy, Raipur 493111, Chhattisgarh, India ( 2017 – till date)
G. Gratitude to Resp. Prof. Shiv Shankar Shukla Sir, Columbia Institute of Pharmacy, Raipur
493111, Chhattisgarh, India (Mentor)
H. Gratitude to Resp. Prof. Atanu Kumar Pati Sir, Vice Chancellor, Gangadhar Meher
University, Sambalpur, Odisha
I. Gratitude to Resp. Prof. Mitashree Mitra Madam, Dept. of Anthropology, PRSU, Raipur,
Chhattisgarh.
J. Gratitude to Resp. Vishal S. Deshmukh Sir (M.Pharm. Supervisor)

25. Q & A Time!

26. Thanks for studying !!!!