The document discusses the rationale and various approaches for prodrug design. It summarizes that prodrugs can be designed to (1) modify physicochemical properties like eliminating volatility, improving stability or solubility; (2) minimize toxicity by masking reactive functional groups; (3) encourage patient acceptance by modifying taste, odor or injection pain; and (4) improve absorption, distribution and site specificity by altering membrane permeability or targeting enzymes. Specific examples are given like methenamine as a urinary tract antiseptic, ester prodrugs of aspirin to reduce gastric toxicity, and amino acid esters of antiviral drugs to enhance solubility. The document highlights how prodrugs can overcome pre-systemic metabolism, provide

1. Rationale of Prodrug Design
Presenting by:
Mr. Purushotham K N
Asst. Professor
Dept. of Pharm.
Chemistry
2021-2022
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2. Rationale of Prodrug Design
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3. Prodrugs to eliminate formulation problems:-
 If the drug is a volatile liquid, it would be more desirable to have it in a solid form so that
it could be formulated as a tablet.
 An inactive solid derivative could be prepared that would be converted in the body to the
active drug.
For ex:-
 Formaldehyde is a flammable, colorless gas with a pungent odor that is used as antiseptic and
disinfectant.
 Solutions of high concentrations of formaldehyde are toxic. Consequently, it
cannot be used directly in medicine.
 It is stable solid that decomposes in aqueous acid.
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4.  In acidic pH media, methenamine hydrolyzes to formaldehyde and ammonium ions.
 Because the pH of urine in the bladder is mildly acidic, methenamine is used as a urinary
tract antiseptic.
 To prevent hydrolysis of this prodrug in the acidic environment of the stomach,
the tablets are enteric coated.
Methenamine
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5. Prodrugs to encourage patient acceptance
 A fundamental tenet in medicine is that in order for a drug to be effective, the patient
has to take it! Painful injections and unpleasant taste or odor are the most common
reasons for the lack of patient acceptance of a drug.
 An excellent example of how a prodrug can increase the potential for patient
acceptance is related to the antibacterial drug clindamycin.
 Whereas clindamycin causes pain on injection, the prodrug clindamycin phosphate is
well tolerated; hydrolysis of the prodrug in vivo occurs with a half life of approximately
10 minutes.
 Also, clindamycin has a bitter taste, so it is not well accepted orally by children.
However, it was found that by increasing the chain length of 2-acyl esters of
clindamycin the taste improved from bitter(acetate ester) to no bitter taste (palmitate
ester).
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6.  The antibacterial sulfa drug sulfisoaxazole(R=H also is bitter tasting , but
sulfisoxazole acetyl (R=COCH3; Gantrisin) is tasteless.
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7. Prodrugs to minimize toxicity:-
 A drug may be toxic in its active form and would have a greater therapeutic index if it were
administered in a nontoxic inactive form that was converted into the active form only at the
site of action.
For ex:-
 The utility of the prodrug approach to lower toxicity of a drug can be found in the design of
aspirin analogs.
 Side effects associated with the use of aspirin are gastric irritation and bleeding.
 The gastric irritation and ulcerogenicity associated with aspirin use may result from an
accumulation of the acid in the gastric mucosal cells.
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8.  Esterification of aspirin (R= alkyl)and other nonsteroidal anti-inflammatory agents
greatly suppresses gastric ulcerogenic activity.
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9. Prodrugs for stability:-
 A drug may be rapidly metabolized and rendered inactive prior when it reaches the site of
action. The structure may be modified to block that metabolism until the drug is at the desired
site.
For ex:-
 Prodrugs protect the drug from the first-pass effect.
 Propranolol is a widely used antihypertensive drug, but because of first-pass elimination, an
oral dose has a much lower bioavailability than does intravenous injection.
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10. Adding ester group on the alcohol will protect it from metabolism.
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11. PRODRUGS FOR IMPROVED WATER SOLUBILITY
The poor aqueous solubility is the major problem as these active agents possess potential
therapeutic activity.
Prodrug approach helps to overcome the problem of aqueous solubility by improving the
dissolution rate.
Dissolution rate is increased by addition of esters and amides of amino acids and
phosphoric acid.
Phosphate esters are widely used to increase the aqueous solubility of orally and parentally
administered drugs.
The amino acid esters and amide prodrugs are also used to improve the aqueous solubility
of active parent drugs.
E.g. valacyclovir and valganciclovir which are valine esters of the antiviral drugs acyclovir
and gancyclovir.. 11

12.  The local anesthetic benzocaine has been converted into water-soluble amide prodrug
forms with various amino acids amidase-catalyzed hydrolysis in human serum occurs
rapidly.
Benzocaine
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13. Prodrugs to improved absorption and distribution:-
 If the desired drug is not absorbed and transported to the target site in sufficient
concentration, it can be made more water soluble or lipid soluble depending on the
desired site of action.
 Once absorption has occurred or when the drug is at the appropriate site of action, the
water or lipid-soluble group is removed enzymatically.
For ex:- Prodrugs to improve absorption through biological membranes.
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14. Epinephrine Dipivefrin
Poor corneal membrane penetration Better corneal penetration
Used in glaucoma
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15. Prodrugs for site specificity:-
 Specificity for a particular organ or tissue can be made if there are high
concentrations of or uniqueness of enzymes present at that site that can cleave the
appropriate appendages from the prodrug and unmask the drug.
 Alternatively, something that directs the drug to a particular type of tissue could be
attached to the drug, which is released after the drug reaches the target tissue.
 Targeting of drugs for a specific site in the body by conversion to a prodrug is
plausible when the physicochemical properties of the parent drug and prodrug are
optimal for the target site.
 When the liphophilicity of a drug is increased, it will improve passive transport of
the drug non specifically to all tissues.
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16. For ex:-
 Oxyphenisatin is a bowel sterilant that is active only when administered
rectally.
 However, when the hydroxyl groups are acetylated the prodrug, oxyphenisatin acetate
can be administered orally and it is hydrolyzed at the site of action in intestines to
oxyphenisatin.
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17. Effect of prodrugs on Pre-systemic Metabolism and Excretion
 The availability of the drug in systemic circulation is affected by pre-systemic
metabolism of the drugs in GIT and the liver.
Which results in the inadequate quantity of drug at the desired site of action or
target.
This problem has been overcome by altering the route of administration and
development of formulation such as sublingual route and by controlled release
formulations.
 Pre-systemic metabolism can be inhibited by the prodrug approach by masking
the metabolically labile functional groups.
E.g. Terbutaline (used to treat asthma) undergoes rapid pre-systemic metabolism,
therefore, it has been prevented by converting its phenolic groups to Bis-dimethyl-
carbamate (bambuterol).
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18. PRODRUG FOR SUSTAIN DRUG ACTION
A Common strategy in the design of slow-release prodrug is to make long-chain
aliphatic esters, because these esters hydrolyse slowly and to inject them
intramuscularly.
Fluphenazine has shorter duration of action (6-8h), but prodrug Fluphenazine
decanoate have duration of activity about month.
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19. Fluphenazine Fluphenazine Decanoate
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20. REFERENCE:
1. TEXTBOOK OF ORGANIC CHEMISTRY OF THE DRUG DESIGN
AND DRUG ACTION BY RICHARD.B.SILVERMAN 2ND
EDITION
2. Dr. M.S Rathore etal. Prodrug Design and Development for
Improved Bioavailability across Biological Barriers published on
Human Journals September 2016 Vol:7, Issue:2
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