EFFECT OF MK-386, A NOVEL INHIBITOR OF TYPE-1 5-ALPHA-REDUCTASE, ALONE AND IN COMBINATION WITH FINASTERIDE, ON SERUM DIHYDROTESTOSTERONE CONCENTRATIONS IN MEN

Two isozymes (types 1 and 2) of 5 alpha-reductase (5 alpha R; EC 1.3.9 9.5), with differential tissue distribution, have been identified in h umans. These enzymes catalyze the reduction of testosterone (T) to dih ydrotestosterone (DHT). The contributions of each of these isozymes to serum and tissue concentrations of DHT remain to be fully defined. Fi nasteride, a selective inhibitor of type 2 5 alpha R, lowers circulati ng DHT levels by similar to 70% in men after treatment with 5 mg daily . MK-386 (4,7 beta-dimethyl-4-aza-5 alpha-cholestan-3-one is a new sel ective inhibitor of type 1 5 alpha R. A single rising dose, alternatin g panel, trial in 16 healthy males (age range, 21-25 yr) studied the e ffect of 0.1-100 mg MK-386. DHT was maximally reduced by 20-30% relati ve to placebo at MK-386 doses of 10 mg or more, orally, by 24 h posttr eatment (P < 0.01 vs. placebo). No consistent effect on T concentratio ns was evident. In a second trial, finasteride (5 mg) was given for 19 days to 10 healthy young men (age range, 24-47 yr); a 25-mg dose of M K-386 was added for 2 days of combination therapy after at least 10 da ys of finasteride treatment. Withdrawal of MK-386 was followed by 5-6 days of finasteride follow-up treatment. Finasteride alone reduced DHT , on the average, by 68.7%, (SE = 3.4%). Addition of MK-386 suppressed DHT by 89.5% (SE = 1.4%) relative to baseline (P < 0.01 os. effect of finasteride alone). Small increases in serum T were observed with fin asteride alone and in combination with MK-386 (similar to 10% and 19%, respectively). These data are consistent with selective 5 alpha R typ e 1 inhibition in man by MK-386 and the prediction that types 1 and 2 5 alpha R account for all, or nearly all, of circulating DHT, Further clinical trials are needed to assess the therapeutic utility of type 1 5 alpha R inhibition as well as that of combined inhibition of types 1 and 2 5 alpha R.