TY - JOUR T1 - Progesterone metabolism in hepatic microsomes. Effect of the cytochrome P-450 inhibitor, ketoconazole, and the NADPH 5 alpha-reductase inhibitor, 4-MA, upon the metabolic profile in human, monkey, dog, and rat. JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 859 LP - 865 VL - 18 IS - 6 AU - D C Swinney Y1 - 1990/11/01 UR - http://dmd.aspetjournals.org/content/18/6/859.abstract N2 - Progesterone was incubated in the presence of NADPH with hepatic microsomes isolated from male and female human, monkey, dog, and rat and the effect of 17 beta-NN-diethylcarbamoyl-4-methyl-4-aza-5 alpha- androstan-3-one (4-MA), an NADPH 5 alpha-reductase inhibitor, and ketoconazole, a cytochrome P-450 inhibitor, upon oxidative metabolism was evaluated. 4-MA caused an increase in detectable oxidative products only with microsomes isolated from rat. An increase in 2 alpha- and 16 alpha-hydroxylation was observed in male rat, and an increase in the formation rate of nine products was observed in female rat. delta 6-Progesterone, 6 beta-, 15 alpha-, 16 alpha-, and 21-hydroxyprogesterone (6 beta-, 15 alpha-, 16 alpha-, and 21-OHP) were common products in both sexes of all species studied. Differences were observed in the formation rate of 2 alpha-, 2 beta-, 6 alpha-, 7 alpha-, and 17 alpha-OHPs. At the 2-carbon, microsomes isolated from both sexes of primates hydroxylated progesterone exclusively at the 2 beta-position. Microsomes from both dog sexes and female rat formed 2 alpha- and 2 beta-OHP, while microsomes isolated from male rat formed exclusively 2 alpha-OHP. 7 alpha-Hydroxylation was detected exclusively in rat, and 6 alpha-hydroxylation was detected in both dog and rat. 17 alpha-Hydroxylase activity in primates was detected only in microsomes from male human. IC50 values associated with ketoconazole inhibition of progesterone metabolism differed among species.(ABSTRACT TRUNCATED AT 250 WORDS) ER -