e-content of Prodrug for M.pharm students.

1. PRODRUG
Presenting By :
Mr. Purushotham K N
Assistant Professor
Dept of Pharmaceutical Chemistry
SAC College of Pharmacy, B G
Nagara.
2021-2022 1

2. Contents
• Introduction
• Definition
• Types of Prodrug
• Prodrugs of functional groups
• Applications
• Advantages and Disadvantages
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3. History of PRODRUG
● Adrien Albert first introduced the term “pro-drug” in. 1958 (Albert, 1958).
● But prodrugs have existed for more than a century.
● First marketed drug in 1899, aspirin is one of the first prodrugs that was
widely used to cure headache. It turns into a substance called salicylic acid
after it enters the body.
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4. What is PRODRUG ?
Pharmacologically Inactive
Compound
Pharmacologically active
Compound
By Enzymatic and/or
chemical conversion
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5. Definition of PRODRUG.
"Biologically inert derivatives of drug molecules that undergo an enzymatic
and/or chemical conversion in-vivo to release the pharmacologically active
parent drug."
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6. Types of PRODRUG
PRODRUG
Based on Structure
of the Drug
Based on Site of
Conversion
Carrier Linked
Prodrugs
Bioprecursor
Prodrugs
Type I Drugs
Type II Drugs
Macromolecular
Prodrugs
Spacer/Linker
Prodrugs
Bipartite
Tripartite
Mutual
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7. Based on Structure of the Drug
Carrier Linked Prodrug
Simple prodrug that contains an active drug linked with a carrier group that is
removed enzymatically. The carrier group must be non-toxic and biologically
inactive when detached from drug.
Active Drug
Inert Carrier Chemical/enzymatically
cleavage in-vivo
Chemical Prodrug formulation
Covalent Bond
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8. ● Carrier Linked Prodrug further classified into three types
1. Bipartite
2. Tripartite
3. Mutual
➔ Bipartite: A bipartite prodrug has a transporter (promoiety) connected
directly with the drug. These prodrugs alter the lipophilicity of the parent
molecule. The active drug can be released by a chemical or enzymatic
hydrolysis reaction, such as tolmetin-glycine prodrug.
DRUG
CARRIER
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9. Ex: Prednisolone Sodium Phosphate, Latanoprost, Dipivefrin and Etoposide
Phosphate.
❖ Prednisolone Sodium Phosphate: The phosphate ester prodrug of the
prednisolone has higher water solubility compared to prednisolone. On the
other hand, the phosphate ester compound is highly polar than the parent
molecule.
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10. ❖ Latanoprost (Xalatan) is a useful drug against glaucoma. The highly
lipophilic isopropyl ester prodrug can be hydrolysed by corneal esterases to
produce the medicinally active, latanoprost.
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11. ➔ Tripartite: This uses a spacer or linker between the drug and a promoiety. In
some examples, the bipartite prodrug can be unstable because of the inherent
nature of the drug-promoiety bonding. This problem can be overcome by
synthesizing a tripartite prodrug.
DRUG
LINKING
STRUCTURE
CARRIER
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12. Ex: Pivampicillin, Bacampicillin.
❖ Pivampicillin consists of pivaloyl-oxy-methyl ester, β-lactam, ampicillin.
The prodrug has a –CH2– linker to connect ampicillin and the pivalic acid.
Pivampicillin has better bioavailability than ampicillin because the ester
group creates higher lipophilicity.
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13. ➔ Mutual: It has two synergistic drugs linked to each other where one drug
serves as the carrier for the other and opposite. Therefore, a mutual prodrug
has two potent agents bound together in such a way that each acts as a
promoiety for the other agent and vice versa.
Ex: Benorylate , Sultamicillin
❖ Benorylate: Aspirin is linked covalently to paracetamol through an ester
linkage. This combination decreases gastric irritation but improves analgesic
power
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14. ❖ Sultamicillin: On hydrolysis by esterase gives ampicillin and sulbactam and
therefore, this is another example of this class of prodrugs.
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15. 2. Bioprecursor Prodrug
These are metabolically activated by oxidation or reduction process rather than
hydrolysis. If a drug contains a carboxylic acid group, the bioprecursor can be a
primary amine that can be metabolized first to the aldehyde and then to the acid.
No carrier is present in this type of example, but the molecule must be
metabolized to undergo functional group transformation.
Ex: Nabumetone (relafen), Prontosil, and Cyclophosphamide Prontosil.
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16. 16
Drugs that inhibits Prostaglandin
biosynthesis by cyclo-oxygenase

17. 3. Macromolecular Prodrug
Also known as polymeric 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.
Ex: p-phenylene diamine mustard is covalently attached to polyamino polymer
backbone polyglutamic acid.
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18. 4. Spacer/Linker Prodrug
The spacer or linker prodrugs can be used when it is difficult to attach
the promoiety with parent drug directly due to steric hindrance or any other
functional barrier. The attachment of spacer with promoiety increases the distance
between parent drug and promoiety. The spacers are cleaved by enzymatic or
chemical action on the bond between promoiety and spacer.
Ex: Fosphenytoin is a linked prodrug of phenytoin with improved aqueous
solubility, Converts with the enzyme known as phosphatase.
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19. Based on Site of Conversion
It’s classified into two types
● Type I Prodrugs (Intracellularly)
● Type II Prodrugs (Extracellularly)
Type I Prodrugs are bioactivated inside the cells (intracellularly). Examples of
these are antiviral nucleoside analogs that must be phosphorylated and the lipid-
lowering statins.
Type II Prodrugs are bioactivated outside cells (extracellularly), especially in
digestive fluids or in the body's circulation system,
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20. Prodrug
Types
Site of
Conversion
Subtypes Tissue/Location of
Conversion
Examples
Type-I Intracellular A Therapeutic Target
Tissues/Cells
Acyclovir, 5-Fluorouracil,
Levodopa
B Metabolic Tissues
(Liver, GI mucosal
cell, Lung, etc)
Carbamazepine, Captopril,
Sulindac.
Type-II Extracellular A GI Fluids Loperamide Oxide,
Oxyphenisatin, Sulfasalazine.
B Systemic
Circulation & Other
extracellular fluid
compartments
Acetylsalicylate,
Bacampicillin, Fosphenytoin.
C Therapeutic Target Acyl-depsi-peptide
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21. Prodrugs of Functional Groups
Different medicinal drugs contain different kinds of functional groups. Prodrugs
are created when these functional groups interact with other functional groups of
non-toxic promoiety.
Some are like
➔ Esters
➔ Amides
➔ Imides
➔ Ring formation derivative
➔ Glycol amide esters
➔ Carbamates
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22. ➔ Esters:
Groups like -COOH, -OH can easily undergo esterification reaction.
Bioavailability of drug can be improved by ester formation. Enzyme esterase
which is present widely in-vivo can easily break up the linkage at target organ so
that targeted delivery is achieved.
Ex: Palmitate ester of Clindamycin.
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23. 23j2

24. ➔ Amides:
The utility of the N-(acyloxy alkoxy carbonyl) derivative is limited due to the
resistance to undergo enzymatic cleave in-vivo. However, certain activated
amides are chemically labile and also certain amides formed with amino acids
may undergo enzymatic cleavage.
Ex: The 𝜸-glutamyl derivatives of dopamine, L-Dopa, N-glycyl derivative.
N-glycyl derivative
Midodrine
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25. ➔ Imides
Ex: N-hydroxy-methylation
The N-hydroxyl methyl derivatives of amides or imide type compounds are more
water soluble than the parent compounds. By replacing a proton bind to nitrogen
atom by a hydroxyl methyl group, intra or intermolecular hydrogen bonding in
such molecules may be increased resulting in a decrease in melting point and
increase in water solubility.
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26. ➔ Ring Formation Derivative
Thiamine quaternary ammonium compounds like Hydantoin, Barbituric acid etc.
can undergo ring opening and show in-vivo pharmacological properties.
➔ Glycol Amide Esters
These are bioavailable products of carboxylic group e.g. Benzoic acid esters.
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27. Carbamates
They exhibit restricted distribution in the body. Carbamates do not have any specific
enzyme for hydrolysis. However, enzymes such as esterase can hydrolyse carbamates e.g.
co-carboxy methyl phenyl ester of Amphetamine.
Other approaches used in the formation of prodrug are phosphamides, glycosides, ethers,
and ketals.
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28. ➔ Application of prodrugs
◆ Pharmaceutical applications
● Improvement of taste
● Improvement of odour
● Reduction of irritation
● Reduction of pain on injection
● Enhancement of drug solubility and dissolution rate
● Enhancement of chemical stability of drug
◆ Pharmacokinetic applications
● Enhancement of provability
● Prevention of pre-systemic metabolism
● Prolongation of duration of action
● Reduction of toxicity
● Site specific drug-delivery
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29. References :
1. Ashutosh Pal.; Bimal Krishna Banik.; Highly Efficient Prodrugs: Design and
Therapeutic Applications, Volume 36, No.06, Published in Oriental Journal
of Chemistry, On 20.12.2020.
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