Roles of Individual Human Cytochrome P450 Enzymes in Drug Metabolism.

ABSTRACT

Our knowledge of the roles of individual cytochrome P450 (P450, CYP) enzymes in drug metabolism has developed considerably in the past 30 years, and this base has been of considerable use in avoiding serious issues with drug interactions and issues due to variations. Some newer approaches are being considered for "phenotyping" of metabolism reactions with new drug candidates. Endogenous biomarkers are being used for non-invasive estimation of levels of individual P450 enzymes. There is also the matter of some remaining "orphan" P450s, which have yet to be assigned reactions. Practical problems that continue in drug development include predicting drug-drug interactions, predicting the effects of polymorphic and other P450 variations, and evaluating inter-species differences in drug metabolism, particularly in the context of "metabolism in safety testing" (MIST) regulatory issues ("disproportionate (human) metabolites"). Significance Statement Cytochrome P450 enzymes are the major catalysts involved in drug metabolism. The characterization of their individual roles has major implications in drug development and clinical practice.