CYP3A ISOFORMS MEDIATED ENANTIOSELECTIVE DRUG METABOLISM WITH HUMAN LIVER MICROSOMES

细胞色素P450（CYP 450）酶参与治疗上有用的药物的各种类型的氧化代谢。CYP 3A亚型是人类肝脏中表达最丰富的P450酶。由于治疗药物通常以含有具有不同药代动力学和药效学特性的对映体的外消旋混合物形式使用，因此对映体选择性肝脏药物代谢导致与1显著不同的对映体比率，从而在解释血浆外消旋药物浓度方面引入了关于其药效学效应的困难。为了研究CYP 3A亚型在一种治疗重要的抗肿瘤药物的对映体选择性肝代谢中的作用。本文研究了CYP 3A介导的单-N-去烯丙基化对映体的体外代谢，发现由Vmax/Km值得到的关于肝内清除率对映体选择性差异的体外酶动力学参数与体内对映体选择性动力学参数吻合较好。基于这些数据，我们得出结论，在体内的对映体选择性的药物代谢介导的CYP 3A可以从体外酶动力学与人肝微粒体获得外推。

Cytochrome P450 (CYP) enzymes are involved in various types of oxidation metabolism of therapcutically useful drugs. CYP3A isoforms are the most abundantly expressed P450 enzymes in human liver. Because therapeutic drugs are often used as a racemic mixture containing enantiomers having distinct pharmacokinetic and pharmacodynamic propertics, an enantioselective hepatic drug metabolism results in an enantiomeric ratio that significantly differs from unity thus introducing diffculties in interpreting plasma racemic drug concentration with regard to its pharmacodynamic effects. In order to investigate the role of CYP3A isoforms in an enantiosclcctive hepatic metabolism of a therapeutically important antiarrhythmic drug. disopyramide, we studied the in vitro metabolism of CYP3A-mediated mono-N-deallylation of the enantiomers of the drug and found that the in vitro enzyme kinetic parameters regarding enantioselective differences in the intrinsic hepatic clearance obtained from Vmax/Km valuce would show a good agreement with the in vivo enantiosclectiive pharmacokineties of the drug. Based upon these data, we concluded that in vivo enantioselective pharmacokinctics of drugs of which metabolism is mediated by CYP3A may be extrapolated from the in vitro enzyme kinetics obtained with human liver microsomes.