This document discusses prodrugs, including their classification, design, applications, and limitations. Prodrugs are biologically inactive compounds that are metabolized in the body to release the active drug molecule. They can improve drug delivery by increasing absorption, modifying distribution, protecting from rapid metabolism, prolonging duration of action, and reducing toxicity. Prodrugs have been successfully used to overcome various pharmaceutical and pharmacokinetic barriers and improve drug efficacy. Recent advances include prodrug formulations in novel drug delivery systems like liposomes and polymeric systems.

2. Prodrugs
DR. RUSHIKESH S. KULKARNI(JR1,PHARMACOLOGY)

3. Introduction
Classification
Designing a prodrug
Applications
Recent advances & future aspects
Limitations
Conclusion

4. Barriers for everything
Successful is the one who overcome
Drug Target site
Pharmaceutical
&
pharmacokinetic
BARRIERS
Decrease in
Efficacy

5. Approaches to increase efficacy
Biological
Physical
Chemical
New drug
Hard and soft drugs
Hard drugs
Resistant to
biotransformation
Increases duration of
action
Soft drugs
Rapid in vivo
biotransformation
Reduces toxicity
Prodrugs

6. Biotransformation prior to pharmacological action_ Adrian Albert(1958)
“A biologically inactive derivative of a parent drug molecule that usually
requires a chemical or enzymatic transformation within the body to
release the active drug, and possesses improved delivery properties over
the parent molecule”

8. Methenamine
(formaldehyde
prodrug)
First
intentional
prodrug
15% of 100
best selling
drugs were
prodrugs
An explosive
increase in the
use of
prodrugs in
drug discovery
and
development
Adrien Albert
First
introduced
the term
“prodrug”

10. • In vivo chemical modification
• Oxidative/Reductive activation
• New compound active or activation
by further metabolism
• Prontosil, Cyclophosphamide are
converted to their active forms viz.
sulphanilamide & phosphoramide
mustard by metabolic reduction and
cyt p450 in liver respectively
AspirinParacetamol
Benorylate/Benorilate
Sulbactum
Ampicillin
Sultamicillin
TolmetinGlycine
•Carrier group is
attached via linker to
drug
•Bacampicillin
Bipartite
•One carrier(group)
•Increased lipophilicity
•Hydrolytic activation
•Tolmetin-glycine prodrug
Tripartite Mutual
• Each drug acts as a
promoiety for the other
agent
• Carrier – synergistic drug
• Benorylate, Sultamicillin
Carrier linked Bioprecursors
Prodrugs
CarrierDrug
Linking
structure

11. •Enalapril
•Slowly deesterified
to enalaprilat
•Longer duration of
action
•Less/no first dose
hypotension
•Potency, no effect of
food on absorption
•Alphacalcidol
•Normally activation
of vit d occurs in
kidney(1)
•Alphacalcidol
requires only 3-
hydroxylation
•Can be effectively
used in renal
impairments
Type IA
•@ cellular targets
•L-DOPA
Type IB
•In liver
•Enalapril,
Alphacalcidol
Type IIA
• In git
• Loperamide oxide,
Sulfsalazine
Type IIB
• In blood
• Fosphenytoin
Type IIC
• Near target
• ADEPT, GDEPT
Type I(Intracellular) Type II(Extracellular)
Based on the site of conversion
• Water soluble
• Injectionstatus
epilapticus
• Very less damage
to intima
• In both saline and
glucose

13. Improving formulation and administration
Enhancing permeability and absorption
Changing the distribution profile
Protecting from rapid metabolism
Increase duration of action
Overcoming toxicity problems

14. Drug Carrier
Target
site
specifier
ADEPT
GDEPT
Carrier/
Specifier
Linker
Spacer
Simple spacers Multiple release spacers
Linker

16. Functional groups used for prodrug designing
Functional
group
Esters Carbamates Amides Oximes
Prodrug of Carboxyl,
Hydroxyl,
Thiol
Carboxyl,
Hydroxyl,
Amine
Carboxylic acids,
Amines
Molecules lacking
Hydroxyl,
Amine or
Carboxyl
Hydrolysis by Esterases Esterases Carboxypeptidase,
Peptidases,
Proteases
Cytochrome p450
Stability to
Hydrolysis
Less stable Moderatly stable Most stable No hydrolysis
Other remarks Most
commonly
used
prodrug
Most often used to
increase oral
absorption.
Targeted drug delivery
Strong base
Increase membrane
permeability &
absorption

18. Absorption
Pharmaceutical applications
Pharmacokinetic applications
Masking taste & odor
Minimizing pain @ injection site
Alteration of drug solubility
Enhancement of chemical stability
Reduction of gi irritation
Change of physical form of the drug
Enhancement of bioavailability
Prevention of pre systemic metabolism
Prolongation of duration of action
Reduction of toxicity
Site specific drug delivery

19. By decreasing
solubility in
saliva
Chloramphenicol
palmitate
Taste
By increasing
boiling point
Diethyl dithio
isophthalate(pro
drug of ethyl
mercaptan)
Odor

20. By increasing
aquous solubility
& pH
Phosphates and
esters of
Clindamycin and
Phenytoin @ pH
12.
Pain
Disodium
phosphate ester of
Betamethasone(1
500*)
Acetylated
sulfonamide moity
added to sodium
salt of
Parecoxib(300*)
Increasing
solubility

21. By modification of
functional group &
changing physical
properties
Bisulfite prodrug of
Azacytidine(antineo
plastic)
Chemical
stability
By avoiding direct
contact, increasing
stimulation of acid
secretion
Decreasing
interference with
mucous layer
Nabumetone(after
absorption)  6-
MNA
G.I.
irritation

22. Liquid form is unsuitable
Liquid drug  Solid Prodrug
By forming a symmetric molecule having higher tendency to crystalise
C2H5SH
Ethyl Mercaptan
COSC2H5
COSC2H5
1,3-Diester

23. Drug Prodrug
Propranolol Propranolol hemisuccinate
Dopamine L-DOPA
Morphine Heroin
Passive diffusion
(absorption)
Bacampicillin
Poor solubility in
gastric fluids
Esters of
Erythromycin
Lipophilicity By temporary
protection of
functional group by
derivatization
Preventing drug –
enzyme complex
formation by
altering
physicochemical
properties
First pass
metabolism

24. Bambuterol Terbutaline by
pseudocholinesterase
Slow hydroxylationsingle
evening dose
Drug(half life) Ester Prodrug(half life)
Testosterone(4 hrs) Testosterone propionate(2 days)
Estradiol (12 hrs) Estradiol propionate(2-3 days)
Fluphenazine (15 hrs) Fluphenazine deacanoate(8 days)
By controlling the
release rate
By controlling rate
of conversion of
prodrug into
active drug.
Duration
of action
Local 
Nabumetone
Local + systemic
 Ibuterol
diisobutyrate ester
of
Terbutaline(glauco
ma)
Toxicity

25. Drug
B
C
D
A Target
Cancer tissue
Eye
Brain
Liver
Prodrug

26. • Tumor specific monoclonal
ab conjugated to drugs
• Ab delivers agent to tumor
cell
• Through receptor mediated
pinocytosis
Targeting ligand conjugated prodrugsEnzyme activated prodrugs
ADEPT GDEPT Ab–drug conjugates Peptide-drug conjugates
• Peptide ligands designed to bind
with a tumor specific Ag or
• Peptide transporter
overexpressed in tumor cell
Cancer targeting by prodrugs
•Ab directed at a tumor
associated Ag which
localizes the enzyme in the
vicinity of tumor
•non toxic prodrug
(substrate) given iv
•Thus conversion only @
tumor site
•Gene for foreign
enzyme delivered into
tumor cells
•Non toxic prodrug
systemically
•Thus conversion only @
tumor site

27. Eye
•Increasing
lipophilicity &
solubility
•Tight corneal
junction
•Precorneal drug
elimination
•Less than 1% drug
reach intra ocular
tissue
Brain
•Using
dihydropyridine or
dihydrotrigonellin
e carrier
•Dopamine linked
to
dihydrotrigonellin
e
•N methyl
pyridinium 2
carbaldoxime (2-
PAM or
Pralidoxime)
Liver
•Receptors AGP,
LDL, HDL,
Insulin,EGF,
Transferrin
•Transporters NCTP,
OATs, OCTs
•Enzymes Many
enzymes, CYP3A4
•Potential for
targeting
•AGP receptor
targeting
Ribavarin, MTX,
Daunorubicin,
Primaquine

29. Liposomal prodrug(EE) Drug (EE)
Triamcolone 21 palmitate(85%) Triamcolone acetonide(5%)
6 Mercaptopurine – glyceryl
monostearate(98%)
6 Mercaptopurine
5 palmitoyl 5 flurouridine(95%) 5 flurouridine(26%)
Prodrugs in novel drug delivery systems
Use of viral vectors
Polymeric prodrugs
Liposomes
Solid lipid nanoparticles
Niosomes
Incorporation of
prodrug in
triglyceride core
releases drug
slowly.
AZT-palmitate
ester prodrug
Vesicles of “Non ionic surfactant”more stable
then phospholipids
In phase III (methacraylamide-doxorubicin)

30. Emergency situations
Liver diseases
Unexpected toxic metabolite

31. 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
In human therapy prodrug designing has given successful results in
overcoming undesirable properties like absorption, nonspecificity,
and poor bioavailability and GI toxicity
Thus, prodrug approach offers a wide range of options in drug design
and delivery for improving the clinical and therapeutic effectiveness
of drug