Prodrug
What is prodrug
A precursor (forerunner) of a drug.
OR
Prodrug , which have no or poor biological
activity, are chemically modified versions
of a pharmacologically active agent, which
must undergo transformation in vivo to
release the active drug.
Why we Develop a
prodrug:
1. Improving aq. Solubility
2. Improving absorption and distribution
3. Site specificity: depends on the presence
of certain enzyme that will release the
active form of drug at the site of action
4. Increase biological stability: mainly by
interfering with drug metabolism
5. Minimize possible toxicity:
◦ Unpleasant taste or odor
◦ Gastric irritation
◦ Pain at the site of injection
6. Improving patient compliance
7. Solve some formulation problems
HISTORY
The first compound fulfilling the classical criteria of a prodrug was
acetanilide, introduced (under the name of Antifebrin) into the
medical practice by Cahn and Hepp in 1867 as an antipyretic agent.
In the body, acetanilide is hydroxylated (aromatic hydroxylation)
to biologically active acetaminophen (paracetamol),the compound
endowed with both antipyreticand analgesic activity.
Another example of a historical prodrug is aspirin (acetylsalicylic
acid), synthesized in 1897 by Felix Hoffman (Bayer, Germany), and
introduced into medicine by Dreser in 1899.
(Aspirin as a prodrug)
• Ester act as precursior
Classification of prodrugs
1.Carrier-linked: here the drug is linked to a
carrier group that can be removed enzymatically:
These are further subdivided into;
Bipartate: if the drug is directly attached to the
carrier group
Tripartate: if there is a linker group between the
drug and the carrier moiety
Mutual prodrug: here two drugs are linked
together, they are synergistic to each other
Classification of prodrugs
2.Bioprecursor: Compound that is
metabolized by molecular modification into
either an active form or into an
intermediate that will be further
metabolized.
Here oxidation is the main metabolic
biotransformation involved in the activation
of bioprecursors.
Reduction and phosphorylation also
involved.
sofosbuvir
Carrier linked prodrugs;
example.
1;Carrier linked prodrugs.
Drugs with alcohol and carboxylic acid
groups:
The common carrier group is the ester
(WHY?)
Availability of esterase enzyme
Possible of either increasing or decreasing the
lipophilicity of the parent drug.
Can be either easily hydrolyzed or relatively stable
ester.
Esters;
Esters are the most commonly employed prodrugs.
Numerous catalytic esterases are present in vivo to
hydrolyze simple esters.
O O
Esterase Drug + HOR
Drug
O R H2O O H
Example;
Chloramphenicol.
Chloramphenicol succinate is prepared by
acylation of chloramphenicol with succinic
anhydride, yielding a water soluble pro-
drug.
Chloramphenicol succinate is an alternative
pro-drug strategy for chloramphenicol
which has a use in surface antibiotic
treatment.
2;Enalapril;
Enalapril Maleate is the maleate salt form
of enalapril, a dicarbocyl-containing peptide and
angiotensin-converting enzyme (ACE) inhibitor
with antihypertensive activity.
As a prodrug, enalapril is converted by de-
esterification into its active form enalaprilat.
Enalaprilat competitively binds to and inhibits
ACE,thereby blocking the conversion of
angiotensin I to angiotensin II.
This prevents the potent vasoconstrictive
actions ofangiotensin II and results in
vasodilation.
Enalapril to enalaprilat;
Conversion of enalapril to
enlaprilate.
2;Bioprecursor prodrugs:
It includes;
Oxidative reaction
Reductive activation
Nucleotide activation
Phosphorylation activation
Decarboxylation activation
1;Oxidation of nabumetone;
Nabumetone is a non-steroidal anti-
inflammatory drug (NSAID) that exhibits
anti-inflammatory, analgesic, and
antipyretic properties in pharmacologic
studies.
As with other non-steroidal anti-
inflammatory agents, its mode of action is
not known; however, the ability to inhibit
prostaglandin synthesis may be involved in
the anti-inflammatory effect.
Nabumetone…………
The parent compound is a prodrug, which
undergoes hepatic biotransformation to the
active component, 6-methoxy-2-
naphthylacetic acid (6MNA) that is a potent
inhibitor of prostaglandin synthesis.
Examples of
bioprecursors:-
1-Oxidation of Nabumetone;
2-Reduction of prontosil to
sulphanilamide;
Sulfanilamide was the active agent
following the breakdown of Prontosil in the
body.
The aim of the search is typically to reduce
the natural toxicity of the parent whilst
improving the medicinal effect.
In 1933 Prontosil was given to the first
patient, an infant with a systemic
staphylococcal infection. The infant
underwent a dramatic cure.
Prontosil to sulphanilamide;
Application with description:-
Prodrug to Improve Patient acceptability ;
One of the reason for poor patient compliance,
particularly in case of children is bitterness,
acidity or causticity of the drug.Two approaches
can be utilized to overcome the bad taste of
drug.
The first is reduction of drug solubility in saliva
and the other is to lower the affinity of drug
towards taste receptor.
Chloramphenicol has a bitter taste, so it is not
well accepted by children.The palmitate ester of
it is less soluble in saliva, so it masks the bitter
taste.
Chloramphenicol
palmitate.
2-Prodrug to improve Stability;
Many drugs are unstable and may either
breakdown on prolonged storage or are
degraded rapidly on administration. Several
drugs may decompose in GIT when used
orally.
Although enteric coatings may be used, it is
also possible to utilize prodrug design to
overcome this problem.
3-Prodrug to improve absorption;
Ampicillin a wide spectrum antibiotic is
readily absorbed orally as the inactive
prodrug, Pivampicillin, Bacampicillin and
Talampicillin which are then converted by
enzymatic hydrolysis to Ampicillin.
4-Prodrug to Improve Membrane
Transport;
Dopamine used for the treatment of
Parkinsonison’s disease can be
improved by administering its prodrug
3, 4-dihydroxy
phenylalanine(Levodopa).
4-Prodrug for Prolonged duration
of action;
Nordazepam, a sedative drug loses
activity quickly due to metabolism and
excretion. A prodrug Diazepam improves
the retention characteristics, due to the
presence of N-methyl group.
Difference
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