used by Albert
a pharmacologically inactive compound that is converted into an active drug by
a metabolic biotransformation
such as hydrolysis- compounds may cause stability problems
can occur before ADME or at specific site in the body
drug- pharmacologically active and uses metabolism for promotion of excretion
Lead modification approach used to correct a flaw in drug
Types of prodrugs
Carrier linked prodrugs and B) Bioprecursors
Carrier linked prodrugs- active drug linked to a carrier group
group- should be labile, non-toxic, biologically inactive
divided to bipartate, tripartate and mutual prodrugs
prodrug with carrier
carrier + linker + prodrug
prodrug- synergistic drugs connected to each other
Bioprecursors- compound metabolized by molecular modification into new compound
which can be drug
resemblance to desired functional group
structural change is required to unmask desired group
is common metabolic biotransformation
Carrier linked prodrugs
ideal drug carrier must
protect the drug until it is at the site of action;
localize the drug at the site of action;
allow for release of the drug chemically or enzymatically;
minimize host toxicity;
biodegradable, biochemically inert, and non-immunogenic;
be easily prepared inexpensively; and
be chemically and biochemically stable in its dosage form
common (biologically labile) functional groups utilized in prodrug design are
Prodrug Active Form of Drug
are the most commonly employed prodrugs.
catalytic esterases are present in vivo to hydrolyze simple esters.
different species have differing amounts and types of esterases with different
substrate specificities and different rates of hydrolysis.
can make it difficult for pharmaceutical companies to generate accurate
preclinical models in which to evaluate their candidate prodrug.
example is the monoethyl ester of enalaprilat, which is called enalapril.
(upper left) was first discovered as an inhibitor of angiotensin converting
enzyme (ACE) and used to treat hypertension.
to its high polarity, note two COOH’s, it was not orally bioavailable, and thus
needed to be administered by injection.
monomethyl ester, enalapril (upper right) is orally bioavailable.
example is the anti-viral agent Oseltamavir (Tamiflu®) shown above
that the oral bioavailability is improved by employing the ethyl ester of the
a strategy is employed for pivampicillin, as shown above.
a strategy can also be used to (temporarily) convert phosphate groups into more
lipophilic ester moieties, as shown above.
of leflunomide to active drug