Zhang Jiang-Wei, Liu Yong, Li Wei, Hao Da-Cheng, Yang Ling
Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, People's Republic of China.
Eur J Clin Pharmacol. 2006 Jul;62(7):497-502. doi: 10.1007/s00228-006-0128-9. Epub 2006 Apr 28.
Medroxyprogesterone acetate (MPA), frequently used in contraception and chemotherapy, was involved in a report of drug-drug interaction (DDI) when co-administrated with phenytoin, doxifluridine and cyclophosphamide. In order to clarify the mechanism of such interaction, an in vitro study was undertaken to evaluate MPA's potential to inhibit cytochrome P450 (CYP) enzymes.
Inhibitory effects of MPA on seven CYPs, including CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2D6, CYP2E1 and CYP3A4, were conducted in human liver microsomes. Time- and NADPH-dependent inhibitions were also tested. DDI potential was predicted according to the [I]/K ( i ) value.
MPA was found to inhibit CYP2C9 and CYP3A4; half inhibition concentration (IC(50)) was 16.1 microM and 31.5 microM, respectively. Slight inhibition was observed on CYP1A2, CYP2A6, CYP2C8 and CYP2D6 with IC(50) of more than 100 microM. MPA exhibited activation rather than inhibition on CYP2E1. Further study revealed that MPA showed a noncompetitive inhibition on CYP2C9 and a competitive inhibition on CYP3A4 with K ( i ) of 9.0 microM and 36 microM, respectively. In addition, MPA was not a mechanism-based inhibitor to any of seven isoforms tested. By using predicted concentration of MPA in liver, [I]/K ( i ) was estimated to be 0.24 and 0.06 for CYP2C9 and CYP3A4, respectively. The concentration of phenytoin co-administrated with MPA was calculated to increase by 24%.
Based on our results, MPA can possibly cause clinically relevant DDI via the inhibition of CYP2C9.
醋酸甲羟孕酮（MPA）常用于避孕和化疗，有报告称其与苯妥英、多西氟尿苷和环磷酰胺合用时会发生药物相互作用（DDI）。为阐明这种相互作用的机制，开展了一项体外研究以评估MPA抑制细胞色素P450（CYP）酶的潜力。
在人肝微粒体中研究MPA对七种CYP酶（包括CYP1A2、CYP2A6、CYP2C8、CYP2C9、CYP2D6、CYP2E1和CYP3A4）的抑制作用。还测试了时间和NADPH依赖性抑制作用。根据[I]/K（i）值预测DDI潜力。
发现MPA可抑制CYP2C9和CYP3A4；半数抑制浓度（IC(50)）分别为16.1微摩尔/升和31.5微摩尔/升。观察到对CYP1A2、CYP2A6、CYP2C8和CYP2D6有轻微抑制，IC(50)超过100微摩尔/升。MPA对CYP2E1表现出激活而非抑制作用。进一步研究表明，MPA对CYP2C9表现出非竞争性抑制，对CYP3A4表现出竞争性抑制，K（i）分别为9.0微摩尔/升和36微摩尔/升。此外，MPA对所测试的七种同工酶均不是基于机制的抑制剂。通过使用肝脏中MPA的预测浓度，CYP2C9和CYP3A4的[I]/K（i）估计分别为0.24和0.06。计算得出与MPA合用时苯妥英的浓度会增加24%。
根据我们的研究结果，MPA可能通过抑制CYP2C9导致具有临床相关性的DDI。
