氯米帕明在体外人肝微粒体中的氮位去甲基代谢(英文)  

N Demethylation of clomipramine in human liver microsomes in vitro 1

作　　者：朱冰[1] 许振华[1] 王伟[1] 周宏灏[1] 

机构地区：[1]湖南医科大学遗传药理学研究所,长沙410078

出　　处：《中国药理学与毒理学杂志》1999年第4期253-259,共7页Chinese Journal of Pharmacology and Toxicology

摘　　要：采用人肝微粒体应用酶促动力学分析，观察特异性细胞色素Ｐ４５０（ＣＹＰ４５０）抑制剂对氯米帕明（ＣＩＭ） Ｎ－去甲基代谢的作用以及ＣＩＭ 去甲基代谢与Ｓ－美芬妥英４′－羟化代谢的相关性，以阐明参与ＣＩＭ Ｎ－去甲基代谢的ＣＹＰ４５０ 的种类， 性质及其在代谢中的作用． 酶促动力学分析结果表明有高亲和力酶及具有底物别构激活特性的低亲和力酶参与了ＣＩＭ 的Ｎ－去甲基代谢． 抑制实验结果表明ＣＹＰ１Ａ２ 特异性抑制剂呋拉茶碱（Ｆｕｒ）主要抑制低浓度ＣＩＭ 的去甲基代谢，ＣＹＰ３Ａ４ 特异性抑制剂醋竹桃霉素（ＴＡＯ）主要抑制高浓度ＣＩＭ 去甲基代谢． 相关实验发现３ μｍ ｏｌ·Ｌ－ １ ＣＩＭ 代谢生成Ｎ－去甲基ＣＩＭ 的速率与２００ μｍ ｏｌ·Ｌ－ １ Ｓ－美芬妥英生成４′－羟基美芬妥英的速率无显著相关性， 提示ＣＹＰ２Ｃ１９ 对于催化人肝微粒体中ＣＩＭ 的去甲基代谢仅起较为次要或很小的作用． 结果表明，ＣＹＰ１Ａ２ 主要参与低浓度ＣＩＭ 在体外人肝微粒体Ｎ－去甲基代谢，ＣＹＰ３Ａ４ 因其底物激活特性主要在高浓度ＣＩＭ的去甲基代谢中起作用，ＣＹＰ２Ｃ１９ 则作用很小．In order to identify the cytochrome P450(CYP450) isoforms responsible for the formation of the N desmethylclomipramine(DCIM) and their relative contributions to the metabolism, the N demethylation of clomipramine(CIM) in human liver microsomes was studied using enzyme kinetic analysis, inhibition and correlation studies. The enzyme kinetic analysis showed that there were at least two enzymes participated in the metabolism of CIM including a high affinity enzyme and a low affinity enzyme. Incubating CIM in the presence of troleandomycin (TAO), a CYP 3A4 selective inhibitor, and furafylline (Fur), a CYP 1A2 selective inhibitor, DCIM formation rate was reduced. By increasing the concentration of TAO, the DCIM formation rate reduced substantially at high substrate concentration. The N demethylation of CIM at 3 μmol·L -1 did not show close correlation with 4′ hydroxylation of S mephenytoin at 200 μmol·L -1 . These results confirm that CYP 1A2 and CYP 3A4 mediate the N demethylation of CIM. CYP 1A2 is the high affinity CYP isoform which catalyzes CIM N demethylation at low substrate concentration in vitro. CYP 3A4, which has allosteric kinetics, plays an important role in the formation of DCIM at high substrate concentration. CYP 2C19 may mediate the N demethylation of CIM only in minor extent.

关 键 词：氯米帕明 呋拉茶碱 肝微粒体 细胞色素P450 

分 类 号：R968[医药卫生—药理学]