CYP3A ISOFORMS MEDIATED ENANTIOSELECTIVE DRUG METABOLISM WITH HUMAN LIVER MICROSOMES

CYP3A 亚型介导的人肝微粒体对映选择性药物代谢

• 批准号: 06672286
• 负责人: ECHIZEN Hirotoshi
• 金额: $ 1.09万
• 依托单位: MEIJI COLLEGE OF PHARMACY (1995)Kitasato University (1994)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1994
• 资助国家: 日本
• 起止时间: 1994 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-06672286/
• 关键词: CYP3A; Human liver microsomes; disopyramide; Enantiomers; キラル

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.

细胞色素P450 （CYP）酶参与治疗有用药物的各种类型的氧化代谢。CYP3A亚型是人类肝脏中表达最丰富的P450酶。由于治疗药物通常作为含有具有不同药代动力学和药效学特性的对映异构体的外消旋混合物使用，因此对映选择性肝脏药物代谢导致对映异构体比例明显不同于统一，从而引入了解释血浆外消旋药物浓度及其药效学效应的困难。为了研究CYP3A亚型在治疗上重要的抗心律失常药物的肝脏代谢中的作用。我们研究了cyp3a介导的药物对映体单n去烯化的体外代谢，发现由Vmax/Km值获得的关于内在肝脏清除率的对映选择性差异的体外酶动力学参数与药物的体内对映性药动学表现出良好的一致性。基于这些数据，我们得出结论，CYP3A介导代谢的药物的体内对映选择性药代动力学可以从人肝微粒体获得的体外酶动力学中推断出来。

项目成果

Echizen H, Mochizuki K, Tani M, Ishizaki T: "Interspecies differences in enantioselective mono-N-dealkylation of disopyramide by human and mouse liver microsomes" J Pharmacol Exp Ther. 268. 1518-1525 (1994)

Echizen H、Mochizuki K、Tani M、Ishizaki T：“人和小鼠肝微粒体对丙吡胺对映选择性单 N-脱烷基化的种间差异”J Pharmacol Exp Ther。

ECHIZEN et al.,: "Interspecies differences in enantioselective mono-N-dealkylation of disopyramide by human and mouse liver" J.Pharmacol.Exp.Ther.268. 1518-1525 (1994)

ECHIZEN 等人：“人和小鼠肝脏对丙吡胺对映选择性单 N-脱烷基化的种间差异”J.Pharmacol.Exp.Ther.268。

Echizen, et al.: "Interspecies differences in enantioselective mono-N-dealkylation of disopyramide by Human and mouse liver microsomes." J Pharmacol Exp Ther. 268. 1518-1525 (1994)

Echizen 等人：“人类和小鼠肝微粒体对丙吡胺的对映选择性单 N-脱烷基化存在种间差异。”

Echizen H et al.: "Interspecis differences in enentioselective mono-N-dealkylation of disopyramide by human and mouse liver microsomes" J Pharmacol Exp Ther. 268. 1518-1525 (1994)

Echizen H 等人：“人类和小鼠肝微粒体对丙吡胺的对映选择性单 N-脱烷基化存在种间差异”J Pharmacol Exp Ther。

Yoshimoto K et al.: "Identification of human CYP isoforms involved in the metabolism of propranolol enantiomers" Br J Clin Pharmacol. 39. 421-431 (1995)

Yoshimoto K 等人：“普萘洛尔对映异构体代谢中涉及的人 CYP 亚型的鉴定”Br J Clin Pharmacol。