Tian G
Department of Enzymology, Glaxo Wellcome Research Institute, Research Triangle Park, NC 27709, USA.
J Pharm Sci. 1996 Jan;85(1):106-11. doi: 10.1021/js950100g.
Finasteride (17 beta-(N-t-butylcarbamoyl)-4-aza-5 alpha-androstan-1-en-3- one), a time-dependent, irreversible inhibitor of human steroid 5 alpha-reductase (5AR), may only reduce dihydrotestosterone levels in humans by approximately 60% at the doses used clinically. A theoretical model was developed to aid in understanding the in vivo efficacy data of finasteride. According to the theory, whether an enzyme can be inhibited in vivo by an irreversible inhibitor is dependent on the value of a ratio of the observed rate of enzyme inhibition over the rate constant for inhibitor elimination. As shown, this ratio should be in excess of 3 for > 95% inhibition of the target in vivo. Subsequent application of the theory to evaluate the in vivo efficacy data of finasteride indicates low effective concentration of finasteride at the inhibition sites and suggests complete inhibition of 5AR 2, but insufficient suppression of 5AR 1 at the clinical doses.
非那雄胺（17β - （N - 叔丁基氨基甲酰基） - 4 - 氮杂 - 5α - 雄甾 - 1 - 烯 - 3 - 酮）是一种时间依赖性、不可逆的人类甾体5α - 还原酶（5AR）抑制剂，在临床使用剂量下，它只能使人体内的双氢睾酮水平降低约60%。开发了一个理论模型来帮助理解非那雄胺的体内疗效数据。根据该理论，一种不可逆抑制剂在体内能否抑制一种酶取决于观察到的酶抑制速率与抑制剂消除速率常数之比的值。如图所示，对于体内> 95%的靶点抑制，该比值应超过3。随后应用该理论评估非那雄胺的体内疗效数据表明，非那雄胺在抑制位点的有效浓度较低，并提示在临床剂量下可完全抑制5AR 2，但对5AR 1的抑制不足。
