Cytochrome P450-Activated Prodrugs: Targeted Drug Delivery

Kristiina   M.   Huttunen; Niina      Mahonen; Hannu      Raunio; Jarkko      Rautio

Abstract

Cytochrome P450 (CYP) enzymes are a superfamily of heme containing proteins that catalyze xenobiotic metabolism phase I reactions. Oxidation reactions are the most common CYP-catalyzed reactions for both endogenous substrates and exogenous compounds, including drugs, although CYP enzymes are capable also to catalyze reduction reactions. Whereas the majority of clinically used drugs are inactivated by CYPs, several prodrugs are bioconverted to their active species by these enzymes. Therefore, this mechanism could be exploited to a greater extend, e.g. by taking advantage of the different CYP enzymes to achieve targeted drug delivery, to improve efficacy or to decrease the unwanted adverse effects of existing and novel drug molecules. This review describes the potential of CYP enzymes in prodrug design and summarizes a wide variety of CYP-activated prodrug structures, which are on the market or under the development. The bioactivation mechanisms of each CYP-activated prodrug structure are described and the specificity for the different forms of CYP enzymes is discussed.

Keywords: Antibody-directed enzyme prodrug therapy (ADEPT), cyclic phosphate, cytochrome P450 enzyme, gene-directed enzyme prodrug therapy (GDEPT), N-oxide, nucleoside, oxazaphosphorine, oxime, prodrug, targeted drug delivery