1. PRODRUG
CONCEPT
PRESENTED BY
Kamrudeen samani
Acharya and B.M Reddy college of pharmacy, Bangalore

2. • CONTENTS
• INTRODUCTION
• OBJECTIVES
• BASIC CONCEPT
• CLASSIFICATION
• DRUG SOLUBILITY

3. Introduction
• Some drugs possess some undesirable physicochemical and
biological properties.
• Drugs are often discontinued due to issues of poor
pharmacokinetic properties or high toxicities
• Their therapeutic efficacy can be improved by eliminating the
undesirable properties while retaining the desirable ones.
• This can be achieved through biological, physical or chemical
means

4. • The Biological approach is to alter the route of administration
which may or may not be acceptable to patient.
• The Physical approach is to modify the design of dosage form
such as controlled drug delivery of drug.
• The best approach in enhancing drug selectivity while
minimizing toxicity, is the chemical approach for design of
pro drugs.

5. Definition
• 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.”
• A prodrug is a chemically modified inert drug precursor,
which upon biotransformation liberates the
pharmacologically active parent compound.

6. Objectives of Prodrug Design
• There are three basic, overlapping objectives in prodrug
research:
1. Pharmaceutical Objectives:
o To improve solubility, chemical stability, and organoleptic
properties
o To decrease irritation and/or pain after local administration,

7. 2. Pharmacokinetic Objectives:
o To improve absorption (oral and by non-oral routes).
o To decrease presystemic metabolism to improve time
profile.
o To increase organ/ tissue-selective delivery of the active
agent.
3. Pharmacodynamic Objectives:
o To decrease toxicity and improve therapeutic index.
o To design single chemical entities combining two drugs (co-
drugs strategy.

8. Prodrugs

9. Prodrug concept
• 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.
• 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.
• 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.

10. • Sometimes drugs are designed to make use of metabolic
processes in order to generate their active form.
• This is done in order to improve some selected property
of the molecule, such as water solubility or ability to cross
a membrane, temporarily.

11. Conversion of Prodrugs
• Metabolism (enzyme dependant)
• Chemical Methods (non-dependant)
• Hydrolysis
• Decarboxylation

12. Classification of Prodrugs

13. Carrier linked prodrug
Carrier linked prodrug consists of the attachment of a carrier
group to the active drug to alter its physicochemical
properties.
The subsequent enzymatic or non-enzymatic mechanism
releases the active drug moiety.
Active
Drug
Inert
Carrier Inert carrier
Drug
Chemical Prodrug
Formation
Chemical/Enzymatic
cleavage in vivo
Covalent
Bond

14. • Carrier-linked prodrugs – drugs that are attached
through a metabolically labile chemical linkage to
another molecule designated as the “promoiety”
• The “promoiety” alters the physical properties of the drug to
increase water or fat solubility or provide site-directed
delivery
• Advantages:
• Increased absorption
• Injection site pain relief
• Elimination of unpleasant taste
• Decreased toxicity
• Decreased metabolic inactivation
• Increased chemical stability
• Prolonged or shortened action

15. Chloramphenicol
N
H
Cl
O
O
O-Na+
O
O
ClOH
O2
N
N
H
Cl
O
H
O
ClOH
O2N
O-Na+
O
O
OH
Esterase
or Water
Chloramphenicol Succinate
Chloramphenicol
Sodium succinate
• Enzymatic and intramolecular spontaneous hydrolysis
• Increased water solubility, ester itself is inactive as an antibiotic
• Promoiety should be nontoxic and easily excreted
• Type of promoiety chosen is a function of properties desired

16. Bipartite prodrug
• It is 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
hydrolytic cleavage either chemically or enzymatically.
• E.g. Tolmetin-glycine prodrug.
TolmetinGlycine
16

17. Tripartite prodrug
The carrier group is attached via linker/spacer to drug.

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

19. AspirinParacetamol
Benorylate
Sulbactu
m
Ampicillin
Sultamicillin

20. Bioprecursors
• 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.
• Eg: phenylbutazone. Phenylbutazone gets metabolized to
oxyphenbutazone that is responsible for the anti
inflammatory activity of the parent drug
• Polymeric Prodrugs
• 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.
• Eg: p–phenylene diamine mustard is covalently attached to
polyamino polymer backbone polyglutamic acid.

21. Bioprecursor Prodrugs
Do NOT contain a carrier or promoiety
Contain latent functionality
Metabolically or chemically transformed into an active drug
Types of activation at are predictable
Oxidative (most common method)
Reductive
Phosphorylation (antiviral agents)
Oxidation Example – Nabumetone – Relafen® – Smith Kline Beecham
CH3
O
CH3O
OH
CH3O
O
Series of oxidative
decarboxylation
Active form of the drug
that inhibits Prostaglandin
biosynthesis by
cyclooxygenase
Non-steroidal
antiinflammatory
Use: Arthritis

22. Novel Classification
 Type I Prodrugs
 Type II Prodrugs
• Type I prodrugs are bio activated inside the cells
(intracellularly). Examples of these are anti-viral nucleoside
analogues that must be phosphorylated and the lipid-
lowering statins.
• Type II prodrugs are bio activated outside cells
(extracellularly), especially in digestive fluids or in the
body's circulation system,

23. Type
Bio
activation site
Subtype
Tissue location of bio
activation
Examples
Type I Intracellular
Type IA
Therapeutic target
tissues/cells
Aciclovir, fluorouracil, cyclopho
sphamide, diethylstilboestrol
diphosphate, L-
DOPA,mercaptopurine, mitomy
cin, zidovudine
Type IB
Metabolic tissues (liver,
GI mucosal cell, lung
etc.)
Carbamazepine, captopril, caris
oprodol, heroin, molsidomine, l
eflunomide, paliperidone,phena
cetin, primidone, psilocybin, suli
ndac, fursultiamine, codeine
Type II Extracellular
Type IIA GI fluids
Loperamide
oxide, oxyphenisatin, sulfasalazi
ne
Type IIB
Systemic circulation
and other extracellular
fluid compartments
Acetylsalicylate, bacampicillin, b
ambuterol, chloramphenicol
succinate, dipivefrin, fosphenyto
in,lisdexamfetamine, pralidoxim
e
Type IIC
Therapeutic target
tissues/cells
ADEPTs, GDEPs, VDEPs

24. Functional Groups in Prodrugs
• Carboxylic acids and Alcohols: Most common type of prodrug
Drug O
Promoiety
O
OH Promoiety
Promoiety O
Drug
O
Drug OH
O
Promoiety OH
O
OH Drug
or
+
+
• Types of esterase enzymes mediating the hydrolysis process
• Ester hydrolase, Lipases, Cholesterol esterases, Acetylcholinesterase,
Carboxypeptidase, Cholinesterase
• Bacterial microflora enzymes
• Wide number of choices of promoiety alcohols available
• Steric, electronic and hydrophobicity properties allow rate and extent of
hydrolysis to be controlled

25. O
CH3
O
O
O
O
OH
CH3
CH3
O
CH3
CH3
CH3
OH
CH3
CH3
OH
O
O
CH3
OH
CH3
OMe
CH3
O
NH(CH3
)2
+-SO4
Erthromycin estolate
Ilosone® - Eli Lilly
caps,tabs, suspension
Antibiotic used to treat
upper and lower respiratory
infections (URI or LRI),
Legionnaire's disease,
skin infections
• Erythromycin is a very bitter substance easily destroyed at acidic pH
• Propionate ester is to increase lipid solubility for improved absorption
• Ester must be hydrolyzed for antibacterial activity
• Lauryl sulfate salt – absorption not affected by food, less bitter after
taste and is acid stable
Functional Groups in Prodrugs

26. Esters Failure as Prodrugs
N
SN
H
O
O
CO2R2
H
R1
R3
R2 = ethyl, propyl, butyl, phenyl
Cephalosporin esters
Esterases
NO REACTION!
N
SN
H
O
O
CO2R2
H
CH3
CH3
R1
R2 = ethyl, propyl, butyl, phenyl
Penicillin esters

27. • Absorption of water soluble vitamin was enhanced by
derivatization of thiolate ion to form lipid soluble prodrugs .
• Dopamine was made useful by making its precursor L-
Dopa. Though L-Dopa is highly polar, it is actively
transported through specific L–amino acid active transport
mechanism and regenerates dopamine by decarboxylation.
• Penta acetyl prodrug of gitoxin has four to five times more
aqueous solubility.
• To increase aqueous solubility esterification with amino
acids is done. Examples of such prodrugs are valacyclovir
and valgancyclovir, which are valine esters of the antiviral
drugs acyclovir and gancyclovir, respectively.

28.  Enhancement of drug solubility and dissolution rate
• The prodrug approach can be used to increase or decrease the
solubility of a drug, depending on its ultimate use.
• Eg: chloramphenicol succinate and chloramphenicol palmitate,
ester prodrugs of chloramphenicol, have enhanced and reduced
aqueous solubility respectively. On the basis of altered solubility,
chloramphenicol sodium succinate prodrug is found suitable for
parenteral administration.
• The prodrug approach is also made useful for better
gastrointestinal absorption.
• Eg: sulindac, a prodrug of sulindac sulfide being more water
soluble with sufficient lipophilicity, makes this drug suitable for
oral administration
• Testosterone - testosterone phosphate ester
• Tetracycline - tetralysine
• Diazepam - diazepam L-lysine ester

29. Enhancement of ophthalmic bioavailability
o Epinephrine - dipivalyl derivative
o Latanoprost and travoprost - isopropyl esters of
latanoprost acid and travoprost acid
Enhancement of percutaneous bioavailability
o Mefenide - mefenide hydrochloride/acetate
Enhancement of topical administration
o Ketolac - Esters of ketolac

30. TO IMPROVE PATIENT ACCEPTIBILITY
REDUCING PAIN DURING ADMINISTRATION BY ALTERING THE
ABSORPTION, DISTRIBUTION,MEATBOLISM AND ELIMINATION OF THE
DRUG.

31. Thank you for your patience!
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