title: Hormonal effects of an orally active 4-azasteroid inhibitor of 5 alpha-reductase in humans.
abstract: The objective of this study was to estimate the minimum in vivo effective oral dose and duration of action of the competitive 5 alpha-reductase inhibitor MK-906, a 4-azasteroid, in humans. Plasma dihydrotesterone (DHT), 5 alpha-androstane-3 alpha,17 beta-diol (AD), and its glucuronide (ADG), as well as urinary androsterone (A) and 5 alpha-pregnane-3 alpha,11 beta, 17 alpha,21-tetrol-20-one (aH4F) were determined in 54 healthy young men before and up to 7 days after a single morning dose of the compound. Twenty-four hours after a single 5- to 40-mg dose (n = 24), plasma DHT levels decreased by a mean of +/- 65%, with slow recovery of DHT levels. Seven days later, DHT remained decreased by +/- 15%. Plasma AD levels decreased to a similar degree, whereas ADG levels decreased by about 75%, indicating inhibition of target tissue 5 alpha-reductase. Testosterone levels did not show any significant variations. The A as well as aH4F excretion in the 24-hour urine test following drug administration decreased by 65%, indicating inhibition of the hepatic 5 alpha-reductase. After a single dose of 1.5 or 0.5 mg, DHT levels decreased by 50% 24 hours after administration, returning to normal within 5-7 days; at this dose, urinary A and aH4F excretion decreased by 50%. A single dose of 0.2 mg appeared to be slightly active as a 5 alpha-reductase inhibitor, but no statistically significant effect on DHT levels was observed after administration of a single 0.04-mg dose. It is concluded that MK-906 is a highly effective 5 alpha-reductase inhibitor in vivo. The effect on plasma DHT lasts for several days after administration of a single oral dose. The data suggest that both hepatic and extrasplanchnic 5 alpha-reductases are inhibited.
authors.affiliation: Department of Endocrinology, University Hospital, Ghent, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Vermeulen
authors.forename: V A
authors.initials: VA
authors.lastname: Giagulli
authors.forename: P
authors.initials: P
authors.lastname: De Schepper
authors.forename: A
authors.initials: A
authors.lastname: Buntinx
authors.forename: E
authors.initials: E
authors.lastname: Stoner
mesh_terms: D058891:5-alpha Reductase Inhibitors; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000728:Androgens / Q000378:metabolism*; D015113:Androstane-3,17-diol / Q000031:analogs & derivatives / Q000097:blood; D000736:Androstenes / Q000008:administration & dosage / Q000494:pharmacology*; D000738:Androsterone / Q000652:urine; D001378:Azasteroids / Q000008:administration & dosage / Q000494:pharmacology*; D002214:Capsules; D013196:Dihydrotestosterone / Q000097:blood; D004341:Drug Evaluation; D018120:Finasteride; D006801:Humans; D007536:Isomerism; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D013260:Steroids, Heterocyclic / Q000494:pharmacology*; D013739:Testosterone / Q000097:blood; D013760:Tetrahydrocortisol / Q000031:analogs & derivatives / Q000652:urine
chemical_list: D058891:5-alpha Reductase Inhibitors; D000728:Androgens; D000736:Androstenes; D001378:Azasteroids; D002214:Capsules; D013260:Steroids, Heterocyclic; D013196:Dihydrotestosterone; D015113:Androstane-3,17-diol; C028895:androstane-3,17-diol glucuronide; C006461:allotetrahydrocortisol; D013739:Testosterone; D018120:Finasteride; D013760:Tetrahydrocortisol; D000738:Androsterone