HORMONAL EFFECTS OF AN ORALLY ACTIVE 4-AZASTEROID INHIBITOR OF 5-ALPHA-REDUCTASE IN HUMANS
HORMONAL EFFECTS OF AN ORALLY ACTIVE 4-AZASTEROID INHIBITOR OF 5-ALPHA-REDUCTASE IN HUMANS
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DOI：
10.1002/pros.2990140106
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发表时间：
1989-01-01
期刊：
影响因子：
2.8
通讯作者：
STONER, E
中科院分区：
文献类型：
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作者：
VERMEULEN, A;GIAGULLI, VA;STONER, E
本研究的目的是估计竞争性5 α-β-D-半乳糖苷的最小体内有效口服剂量和作用持续时间。还原酶抑制剂MK-906，一种4-氮杂星。血浆双氢睾酮（DHT），5 α-雄甾烷-3 α，17. β-二醇（AD）及其葡糖苷酸（ADG），以及尿雄酮（A）和5 α-正辛烷-3 α，11. β- 17. α，测定了54名健康青年男子在服用21-四醇-20-酮（aH_4F）前和服用该化合物后7天内的血药浓度。在单次5- 40-mg剂量（n = 24）后24小时，血浆DHT水平平均下降± 0.5%。65%，DHT水平恢复缓慢。7天后，DHT仍下降了±。百分之十五血浆AD水平降低至相似程度，而ADG水平降低约75%，表明靶组织5 α-ADG的抑制。还原酶。睾酮水平未显示任何显著变化。在药物给药后的24小时尿试验中，A和aH 4F的排泄减少了65%，表明肝5 α-F的抑制。还原酶。单次给药1.5或0.5 mg后，给药后24小时，DHT水平下降50%，5-7天内恢复正常;在此剂量下，尿A和aH 4F排泄量下降50%。0.2mg的单次剂量作为5 α-β-葡糖苷酸似乎有轻微活性。还原酶抑制剂，但在单次给药0.04 mg后，未观察到对DHT水平的统计学显著影响。可以得出结论，MK-906是高效的5-α还原酶抑制剂。单次口服给药后，对血浆DHT的影响持续数天。数据表明，肝和外胎盘5 α-还原酶被抑制。
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 dihydrotestosterone (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.