Ketoconazole inhibition of progesterone oxidation by the rabbit

Ketoconazole, a known cytochrome P-450 inhibitor, inhibited both progesterone ring hydroxylation and side-chain oxidation to steroidal acids. Progesterone 21 6 beta- and 16 alpha-hydroxylase activities of rabbit liver microsomes were inhibited 50% by ketoconazole at concentrations between 10(-5) and 10(-4) M. Steroid acid formation was similarly inhibited at a 10(-5) M concentration. Ketoconazole administration to rabbits produced a significant reduction in the urinary excretion of acidic metabolites of [3H]deoxycorticosterone and [14C]progesterone by approximately 50 and 75% respectively. The differential effect of ketoconazole in vivo may indicate that more than one acidic metabolite pathway may be operative.