Schwartz J I, Van Hecken A, De Schepper P J, De Lepeleire I, Lasseter K C, Shamblen E C, Winchell G A, Constanzer M L, Chavez C M, Wang D Z, Ebel D L, Justice S J, Gertz B J
Merck Research Laboratories, Rahway, New Jersey 07065, USA.
J Clin Endocrinol Metab. 1996 Aug;81(8):2942-7. doi: 10.1210/jcem.81.8.8768856.
Two isozymes (types 1 and 2) of 5 alpha-reductase (5 alpha R; EC 1.3.99.5), with differential tissue distribution, have been identified in humans. These enzymes catalyze the reduction of testosterone (T) to dihydrotestosterone (DHT). The contributions of each of these isozymes to serum and tissue concentrations of DHT remain to be fully defined. Finasteride, a selective inhibitor of type 2 5 alpha R, lowers circulating DHT levels by approximately 70% in men after treatment with 5 mg daily. MK-386 (4,7 beta-dimethyl-4-aza-5 alpha-cholestan-3-one) is a new selective inhibitor of type 1 5 alpha R. A single rising dose, alternating panel, trial in 16 healthy males (age range, 21-25 yr) studied the effect of 0.1-100 mg MK-386. DHT was maximally reduced by 20-30% relative to placebo at MK-386 doses of 10 mg or more, orally, by 24 h posttreatment (P < 0.01 vs. placebo). No consistent effect on T concentrations was evident. In a second trial, finasteride (5 mg) was given for 19 days to 10 healthy young men (age range, 24-47 yr); a 25-mg dose of MK-386 was added for 2 days of combination therapy after at least 10 days of finasteride treatment. Withdrawal of MK-386 was followed by 5-6 days of finasteride follow-up treatment. Finasteride alone reduced DHT, on the average, by 68.7% (SE = 3.4%). Addition of MK-386 suppressed DHT by 89.5% (SE = 1.4%) relative to baseline (P < 0.01 vs. effect of finasteride alone). Small increases in serum T were observed with finasteride alone and in combination with MK-386 (approximately 10% and 19%, respectively). These data are consistent with selective 5 alpha R type 1 inhibition in man by MK-386 and the prediction that types 1 and 2 5 alpha R account for all, or nearly all, of circulating DHT. Further clinical trials are needed to assess the therapeutic utility of type 1 5 alpha R inhibition as well as that of combined inhibition of types 1 and 2 5 alpha R.
在人类中已鉴定出5α-还原酶（5αR；EC 1.3.99.5）的两种同工酶（1型和2型），它们在组织中的分布存在差异。这些酶催化睾酮（T）还原为二氢睾酮（DHT）。每种同工酶对血清和组织中DHT浓度的贡献仍有待充分明确。非那雄胺是2型5αR的选择性抑制剂，男性每日服用5毫克治疗后，循环中的DHT水平可降低约70%。MK-386（4,7β-二甲基-4-氮杂-5α-胆甾烷-3-酮）是一种新型的1型5αR选择性抑制剂。在16名健康男性（年龄范围21 - 25岁）中进行的一项单剂量递增、交替分组试验，研究了0.1 - 100毫克MK-386的效果。口服MK-386剂量为10毫克或更高时，相对于安慰剂，DHT在治疗后24小时最大降低20% - 30%（与安慰剂相比，P < 0.01）。对T浓度未观察到一致的影响。在第二项试验中，10名健康年轻男性（年龄范围24 - 47岁）服用非那雄胺（5毫克）19天；在非那雄胺治疗至少10天后，添加25毫克剂量的MK-386进行2天的联合治疗。停用MK-386后，继续进行5 - 6天的非那雄胺后续治疗。单独使用非那雄胺时，DHT平均降低68.7%（标准误 = 3.4%）。添加MK-386后，相对于基线，DHT抑制率为89.5%（标准误 = 1.4%）（与单独使用非那雄胺的效果相比，P < 0.01）。单独使用非那雄胺以及与MK-386联合使用时，血清T均有小幅升高（分别约为10%和19%）。这些数据与MK-386对男性1型5αR的选择性抑制作用一致，也与1型和2型5αR占循环中所有或几乎所有DHT的预测相符。需要进一步的临床试验来评估抑制1型5αR以及联合抑制1型和2型5αR的治疗效用。
