CYTOCHROME-P450 INHIBITORS - EVALUATION OF SPECIFICITIES IN THE IN-VITRO METABOLISM OF THERAPEUTIC AGENTS BY HUMAN LIVER-MICROSOMES

Identifying selective inhibitors of cytochrome P450 isoforms is a usef ul tool in defining the role of individual cytochrome P450s in the met abolism process. In this study, nine chemical inhibitors were selected based on literature data and were examined for their specificity towa rd cytochrome P450-mediated reactions in human liver microsomes. Furaf yiline was a potent, mechanism-based inhibitor for CYP1A2-mediated phe nacetin O-deethylation. The probes sulfaphenazole (CYP2C9) and quinidi ne (CYP2D6) selectively inhibited tolbutamide methylhydroxylation and bufuralol 1'-hydroxylation, respectively. Additionally, the CYP2E1-cat alyzed chlorzoxazone 6-hydroxylation was significantly inhibited by di ethyldithiocarbamate. Of the CYP3A4 inhibitor probes used, troleandomy cin proved to be the most specific for testosterone 6 beta-hydroxylati on.