Kondo Y, Homma Y, Aso Y, Kawabe K, Mieda M, Takahashi H
Department of Urology, Faculty of Medicine, University of Tokyo, Japan.
Prostate. 1996 Sep;29(3):146-52. doi: 10.1002/(SICI)1097-0045(199609)29:3<146::AID-PROS1>3.0.CO;2-C.
Mechanisms of relative potency in direct action of antiandrogens have not been fully elucidated. Using castrated rats, the effects of antiandrogens on the prostatic weight gain induced by exogenous testosterone (T), and on T uptake into prostatic cells were examined. Tested antiandrogens were cyproterone acetate, chlormadinone acetate, a new steroidal antiandrogen, 17acetoxy-6-chloro-2-oxa-4,6-pregnadiene-3,20-dione (TZP-4238), and one nonsteroidal type, flutamide (FL). Suppression of prostatic weight gain, T uptake and serum concentrations of compounds, correlated well each other among steroidal antiandrogens, while FL was five times more active in suppressing weight gain than TZP-4238, associated with a lower nuclear distribution of androgen. The results suggest that 1) suppression of T uptake is a major and common mechanism of steroidal antiandrogens and the relative potency is attributable to pharmacokinetic characteristics in vivo, and 2) FL suppress s nuclear T uptake more specifically than steroidal antiandrogens.
抗雄激素直接作用的相对效价机制尚未完全阐明。利用去势大鼠，研究了抗雄激素对外源性睾酮（T）诱导的前列腺重量增加以及对前列腺细胞摄取T的影响。所测试的抗雄激素有醋酸环丙孕酮、醋酸氯地孕酮、一种新的甾体类抗雄激素17-乙酰氧基-6-氯-2-氧杂-4,6-孕二烯-3,20-二酮（TZP-4238）以及一种非甾体类的氟他胺（FL）。在甾体类抗雄激素中，前列腺重量增加的抑制、T摄取的抑制以及化合物的血清浓度之间相互关联良好，而氟他胺在抑制重量增加方面的活性比TZP-4238高5倍，且与雄激素较低的核分布相关。结果表明：1）抑制T摄取是甾体类抗雄激素的主要且常见机制，相对效价归因于体内的药代动力学特征；2）氟他胺比甾体类抗雄激素更特异性地抑制核T摄取。
