ROLES OF HUMAN P450 ENZYMES IN DRUG OXIDATIONS USING RECOMBINANT P450S AND HUMAN LIVER MICROSOMES

Abstract

Troglitazone, a new oral antidiabetic drug, is reported not to be oxidized by cytochrome P450 (P450 or CYP) enzymes. However, cDNA-expressed CYP2C8 and CYP3A4 were active in catalyzing formation of a quinone-type metabolite. Intensity of inhibitory effects of specific P450 inhibitors and antiP450 antibodies on the quinone-type metabolite formation depended on human liver samples and their P450 status. Azelastine, an antiallergy drug, was N-demethylated by CYP2D6, CYP3A4 and CYP1 A2 in human liver microsomes biphasically. Human intrinsic clearance was predictable from kinetic parameters using cDNA-expressed P450 enzymes. The results suggest that different P450 enzymes in human liver have major roles in quinone-type metabolite formation from troglitazone and azelastine N-demethylation and that the hepatic contents of these P450 forms determine which P450 enzymes play the major roles in drug metabolism in individual humans.