Prodrugs

• Initially used by Albert

• Is a pharmacologically inactive compound that is converted
into an active drug by a metabolic biotransformation

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 • Can be enzymatic/non-enzymatic

• Non-enzymatic such as hydrolysis- compounds may cause

stability problems
• Conversion can occur before ADME or at specific site in the body
• Soft drug- pharmacologically active and uses metabolism for
promotion of excretion
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 Why prodrug
Lead modification approach used to correct a flaw in drug candidate
•Aqueous solubility
•Absorption and distribution
•Site specificity

•Instability
•Prolonged release

•Toxicity
•Poor patient acceptability
•Formulation problems
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 Types of prodrugs

• A) Carrier linked prodrugs and B) Bioprecursors

• A) Carrier linked prodrugs- active drug linked to a carrier group
• Carrier group- should be labile, non-toxic, biologically inactive

• Further divided to bipartate, tripartate and mutual prodrugs

• Bipartate- prodrug with carrier
• Tripartate- carrier + linker + prodrug

• Mutual prodrug- synergistic drugs connected to each other

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 Types of prodrugs
• B) Bioprecursors- compound metabolized by molecular
modification into new compound which can be drug
• No resemblance to desired functional group
• Drastic structural change is required to unmask desired group
• Oxidation is common metabolic biotransformation

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 Carrier linked prodrugs
• An ideal drug carrier must
• (1) protect the drug until it is at the site of action;
• (2) localize the drug at the site of action;
• (3) allow for release of the drug chemically or enzymatically;

• (4) minimize host toxicity;

• (5) biodegradable, biochemically inert, and non-immunogenic;
• (6) be easily prepared inexpensively; and

• (7) be chemically and biochemically stable in its dosage form

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 • Most common (biologically labile) functional groups utilized in
prodrug design are shown above.
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 Prodrug Active Form of Drug

• Esters are the most commonly employed prodrugs.

• Numerous catalytic esterases are present in vivo to hydrolyze

simple esters.

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 • However, different species have differing amounts and types of
esterases with different substrate specificities and different rates
of hydrolysis.
• This can make it difficult for pharmaceutical companies to
generate accurate preclinical models in which to evaluate their
candidate prodrug. 9
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 Prodrugs

• One example is the monoethyl ester of enalaprilat, which is

called enalapril.

• Enalaprilate (upper left) was first discovered as an inhibitor of

angiotensin converting enzyme (ACE) and used to treat
hypertension.
• Due to its high polarity, note two COOH’s, it was not orally
bioavailable, and thus needed to be administered by injection.
• The monomethyl ester, enalapril (upper right) is orally
bioavailable.

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 • Another example is the anti-viral agent Oseltamavir (Tamiflu®)
shown above
• Notice that the oral bioavailability is improved by employing
the ethyl ester of the carboxylic acid
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 Famciclovir

Diacetate ester of the corresponding diol

(penciclovir)

• Conversely, such a strategy can also be used to convert an

alcohol to a more lipophilic moiety, as shown above.

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 • Such a strategy is employed for pivampicillin, as shown above.

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 • Such a strategy can also be used to (temporarily) convert
phosphate groups into more lipophilic ester moieties, as
shown above.
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 Prodrugs
• To minimize toxicity To Encourage Patient Acceptance

• To eliminate formulation problems Improved absorption

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 Prodrugs
• Increased water solubility

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 Bioprecursors
• Prontosil to sulfonamides

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 Bioprecursors

• Activation of leflunomide to active drug

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 Bioprecursors

• Sulfation activation Decarboxylation activation

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