Vol. 29, Issue 6, 837-842, June 2001

Clotrimazole is a Selective and Potent Inhibitor of Rat Cytochrome P450 3A Subfamily-Related Testosterone Metabolism

Valerie K. Turan, Vladimir M. Mishin, and Paul E. Thomas

Joint Graduate Program in Toxicology, Rutgers, The State University of New Jersey/University of Medicine and Dentistry of New JerseyRobert Wood Johnson Medical School, Piscataway, New Jersey (V.K.T., P.E.T.); and Laboratory for Cancer Research, College of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey (V.M.M., P.E.T.)

In this study, clotrimazole (CTZ) and ketoconazole (KTZ) were evaluated for their inhibition of testosterone metabolism catalyzed by rat hepatic microsomes differentially expressing certain cytochrome P450 enzymes. The objective was to compare the inhibitory potencies using hepatic microsomes from adult female rats treated with dexamethasone (F-DEX) and hepatic microsomes from vehicle-treated adult male rats (M-VEH), which are known to contain high levels of isozymes CYP3A1 (3A23) and 3A2, respectively. The results demonstrate that CTZ is a very potent and selective inhibitor of the 6-hydroxylation of testosterone, a CYP3A-mediated reaction, in all rat metabolic systems tested. The IC₅₀ value was 9.7 nM in F-DEX, and 6.7 nM in M-VEH for CTZ. The in vitro inhibitory potency for CTZ significantly exceeds the same parameters for KTZ, a well established specific inhibitor of human CYP3A-mediated reactions. It was found that the IC₅₀ values of KTZ in F-DEX and M-VEH were 69 and 780 nM, respectively. These values for KTZ are 10-fold and 100-fold higher, respectively, than for CTZ. CTZ, at the concentration that inhibits 90% and more of CYP3A-mediated reactions (40 nM), has less than a 10% inhibitory effect on the activities of other rat liver enzymes, such as CYP1A1, -1A2, -2A1, -2B1, -2B2, -2C11, and -2E1. In summary, CTZ is a more potent and selective inhibitor of all CYP3A-mediated reactions than KTZ in rat hepatic microsomes.