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MK-386, an Inhibitor of 5-Reductase Type 1, Reduces Dihydrotestosterone Concentrations in Serum and Sebum without Affecting Dihydrotestosterone Concentrations in Semen¹

Merck Research Laboratories (J.I.S., W.K.T., D.Z.W., D.L.E., L.A.G., A.D., B.J.G.), Rahway, New Jersey 07065; and Pharmaco:International, Inc. (B.H.), Austin, Texas 78704

Address all correspondence and requests for reprints to: Barry J. Gertz, M.D., Ph.D., Merck Research Laboratories, P.O. Box 2000, RY33–600, Rahway, New Jersey 07065-0900.

Two isozymes (types 1 and 2) of 5-reductase (5R; EC 1.3.99.5), with differential tissue distribution, catalyze the reduction of testosterone (T) to dihydrotestosterone (DHT) in humans. This study examined sequentially increasing oral doses of MK-386 (4,7ß-dimethyl-4-aza-5-cholestan-3-one), an azasteroid that specifically inhibits the human 5R1 isozyme in vitro. Finasteride, a selective inhibitor of 5R2, was included for comparison. One hundred men were evaluated in a double blind, randomized, placebo-controlled, sequential, increasing dose, parallel group trial. Ten to 20 subjects received MK-386, and 2 to 5 received placebo in each of 6 panels. In 1 panel, 10 subjects received finasteride (5 mg), and 5 received placebo. Treatments 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 daily. Serum, sebum, and semen DHT concentrations and serum and sebum T concentrations were measured before and after treatment.

The mean changes 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 < 0.05 vs. placebo), and -22.2% (P < 0.05 vs. placebo), respectively. No significant alterations in serum T were observed after any dose of MK-386. Serum DHT fell 65.8% from the baseline 14 days after finasteride treatment (P < 0.05 vs. 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 vs. placebo), and -49.1% (P < 0.05 vs. placebo) for the placebo and 0.5, 5, 20, and 50 mg MK-386 groups, respectively. Finasteride also reduced sebum DHT, but to a lesser extent (-14.9%; P < 0.05 vs. placebo). Reciprocal increases in sebum T concentration were noted at 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-androstanediol glucuronide values were 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 aminotransferase elevations were observed in two subjects at the 50-mg dose.

The differential responses in serum, sebum, and semen DHT concentrations associated with MK-386 and finasteride treatments are consistent with those changes anticipated for selective inhibitors of the human 5R isozymes. Dose-dependent suppression of sebum DHT by a 5R1 inhibitor suggests the potential utility of such compounds in the treatment of acne.

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