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Hormonal effects of an orally active 4‐azasteroid inhibitor of 5α‐reductase in humans
Author(s) -
Vermeulen A.,
Giagulli V. A.,
De Schepper P.,
Buntinx A.,
Stoner E.
Publication year - 1989
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.2990140106
Subject(s) - endocrinology , medicine , androsterone , dihydrotestosterone , testosterone (patch) , oral administration , excretion , chemistry , hormone , morning , androgen , steroid
The objective of this study was to estimate the minimum in vivo effective oral dose and duration of action of the competitive 5α‐reductase inhibitor MK‐906, a 4‐azasteroid, in humans. Plasma dihydrotestosterone (DHT), 5α‐androstane‐3α, 17β‐diol (AD), and its glucuronide (ADG), as well as urinary androsterone (A) and 5α‐pregnane‐3α, 11β, 17α, 21‐tetrol‐20‐one (aH 4 F) 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 5α‐reductase. Testosterone levels did not show any significant variations. The A as well as aH 4 F excretion in the 24‐hour urine test following drug administration decreased by 65%, indicating inhibition of the hepatic 5α‐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 aH 4 F excretion decreased by 50%. A single dose of 0.2 mg appeared to be slightly active as a 5α‐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 5α‐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 5α‐reductases are inhibited.