ABSTRACT

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 437 Modifications Employing Hydrophilic Functional Groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 438 Modifications Employing Amino Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 446 Modifications Employing Hydrophobic Functional Groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449 Modifications Involving Polymers and Macromolecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 452 Chemical and Enzymatic Lability of the Promoiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 457 Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 459 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 459

Prodrug is a term used by Albert to describe a compound that must undergo bioconversion before exerting its pharmacological effect (Albert, 1958, 1964). The term, as applied here, will refer to a drug with a covalently bound, inactive moiety (the promoiety) that provides the desired pharmaceutical properties, where the promoiety must be removed upon administration to regenerate the parent drug. Enzymatic and chemical processes are available for removal of the inactive moiety, and these may guide or limit the selection of the promoiety. As an example, esterases are present throughout the body and can be utilized in the hydrolysis of an ester functional group in a prodrug for a drug bearing a carboxylic acid or an alcohol group (Colaizzi and Pitlick, 1982). The reconversion of the prodrug to the parent compound by enzymatic means requires that the enzyme be capable of cleaving the promoiety-drug linkage. Thus, prodrugs typically must exhibit a long shelf life in aqueous media, and be rapidly reconverted to the parent drug under physiological conditions (Lallemand et al., 2005b). Chemical reversal, in vitro or in vivo, may demonstrate less intersubject variability than do methods that rely on biochemical reversal (Notari, 1985).