title: MK-386, an inhibitor of 5alpha-reductase type 1, reduces dihydrotestosterone concentrations in serum and sebum without affecting dihydrotestosterone concentrations in semen.
abstract: Two isozymes (types 1 and 2) of 5alpha-reductase (5alphaR; 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 (4,7beta-dimethyl-4-aza-5alpha-cholestan-3-one), an azasteroid that specifically inhibits the human 5alphaR1 isozyme in vitro. Finasteride, a selective inhibitor of 5alphaR2, 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 3alpha-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 5alphaR isozymes. Dose-dependent suppression of sebum DHT by a 5alphaR1 inhibitor suggests the potential utility of such compounds in the treatment of acne.
authors.affiliation: Merck Research Laboratories, Rahway, New Jersey 07065, USA.
authors.forename: J I
authors.initials: JI
authors.lastname: Schwartz
authors.forename: W K
authors.initials: WK
authors.lastname: Tanaka
authors.forename: D Z
authors.initials: DZ
authors.lastname: Wang
authors.forename: D L
authors.initials: DL
authors.lastname: Ebel
authors.forename: L A
authors.initials: LA
authors.lastname: Geissler
authors.forename: A
authors.initials: A
authors.lastname: Dallob
authors.forename: B
authors.initials: B
authors.lastname: Hafkin
authors.forename: B J
authors.initials: BJ
authors.lastname: Gertz
mesh_terms: D058891:5-alpha Reductase Inhibitors; D000293:Adolescent; D000328:Adult; D015113:Androstane-3,17-diol / Q000031:analogs & derivatives / Q000097:blood; D001378:Azasteroids / Q000494:pharmacology*; D013196:Dihydrotestosterone / Q000097:blood* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018120:Finasteride / Q000494:pharmacology; D006801:Humans; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D008875:Middle Aged; D012629:Sebum / Q000378:metabolism*; D012661:Semen / Q000378:metabolism*; D013739:Testosterone / Q000097:blood
chemical_list: C090665:4,7beta-dimethyl-4-azacholestan-3-one; D058891:5-alpha Reductase Inhibitors; D001378:Azasteroids; D004791:Enzyme Inhibitors; D013196:Dihydrotestosterone; D015113:Androstane-3,17-diol; C028895:androstane-3,17-diol glucuronide; D013739:Testosterone; D018120:Finasteride; D007986:Luteinizing Hormone