MK-386, AN INHIBITOR OF 5-ALPHA-REDUCTASE TYPE-1, REDUCES DIHYDROTESTOSTERONE CONCENTRATIONS IN SERUM AND SEBUM WITHOUT AFFECTING DIHYDROTESTOSTERONE CONCENTRATIONS IN SEMEN

Two isozymes (types 1 and 2) of 5 alpha-reductase (5 alpha R; EC 1.3.9 9.5), with differential tissue distribution, catalyze the reduction of testosterone (T) to dihydrotestosterone (DHT) in humans. This study e xamined sequentially increasing oral doses of MK-386 (4,7 beta-dimethy l-4-aza-5 alpha-cholestan-3-one), an azasteroid that specifically inhi bits the human 5 alpha R1 isozyme in vitro. Finasteride, a selective i nhibitor of 5 alpha R2, was included for comparison. One hundred men w ere evaluated in a double blind, randomized, placebo-controlled, seque ntial, increasing dose, parallel group trial. Ten to 20 subjects recei ved MK-386, and 2 to 5 received placebo in each of 6 panels. In 1 pane l, 10 subjects received finasteride (5 mg), and 5 received placebo. Tr eatments were given once daily for 14 days, except in 1 panel in which MK-386 was administered 10 mg twice daily for comparison to 20 mg dai ly. Serum, sebum, and semen DHT concentrations and serum and sebum T c oncentrations were measured before and after treatment. The mean chang es from baseline on day 14 for serum DHT after placebo and 0.1, 0.5, 5 , 20, and 50 mg MK-386 were 6.9%, 4.6%, - 2.7%, -1.2%, -14.1% (P < 0.0 5 vs. placebo), and -22.24% (P < 0.05 vs. placebo), respectively. No s ignificant alterations in serum T were observed after any dose of MK-3 86. Serum DHT fell 65.8% from the baseline 14 days after finasteride t reatment (P < 0.05 us. placebo). The mean changes from baseline on day 14 in sebum DHT were 5.0%, 3.0%, -25.4% (P < 0.05 vs. placebo), -30.1 % (P < 0.05 us. placebo), and -49.1% (P < 0.05 us. placebo) for the pl acebo and 0.5, 5, 20, and 50 mg MK-386 groups, respectively. Finasteri de also reduced sebum DHT, but to a lesser extent (-14.9%; P < 0.05 us . placebo). Reciprocal increases in sebum T concentration were noted a t doses of 5 mg or more of MK-386, but not with finasteride. The mean reduction in semen DHT with 5 mg finasteride was approximately 88% (P < 0.01 vs. placebo); no significant change in semen DHT was noted with 20 or 50 mg MK-386. Serum 3 alpha-androstanediol glucuronide values w ere also reduced after the 20- and 50-mg MK-386 treatments in parallel with the changes in serum DHT. No meaningful changes were observed in serum LH after MK-386 treatment. MK-386 was generally well tolerated by all subjects; reversible aspartate aminotransferase/alanine aminotr ansferase elevations were observed in two subjects at the 50-mg dose. The differential responses in serum, sebum, and semen DHT concentratio ns associated with MK-386 and finasteride treatments are consistent wi th those changes anticipated for selective inhibitors of the human 5 a lpha R isozymes. Dose-dependent suppression of sebum DHT by a 5 alpha R1 inhibitor suggests the potential utility of such compounds in the t reatment of acne.