外消旋普罗帕酮在经诱导的大鼠肝微粒体中N-去丙基化的立体选择性  

Stereoselectivity of racemic propafenone in N depropylation with rat liver microsomes pretreated by different inducers

作　　者：姚彤炜[1] 周权[1] 胡晓喻 曾苏[1] 

机构地区：[1]浙江大学药学院,浙江杭州310031

出　　处：《中国药理学与毒理学杂志》2000年第6期440-444,共5页Chinese Journal of Pharmacology and Toxicology

基　　金：国家自然科学基金资助项目!(39370 80 5 );浙江省自然科学基金资助项目!(RC970 16 )

摘　　要：:采用对照及 β-萘黄酮 (β- NF)或地塞米松(Dex)诱导的大鼠肝微粒体 ,应用 GITC柱前衍生化 ,反相高效液相色谱法研究了消旋普罗帕酮〔(R/S) - PPF〕体外代谢的立体选择性 .实验结果表明 ,在 Dex,β- NF诱导的微粒体中有 N-去丙基普罗帕酮生成。在 β- NF,Dex预处理组 ,(R/S) - PPF低浓度时的经肝微粒体代谢具有立体选择性 ,R(- )对映体的清除大于 S(+)对映体 ,高浓度时的代谢无立体选择性 .R(- )对映体的 Km 值显著低于 S(+)对映体 ,而 Vmax值无显著性差异 .在 Dex预处理组中的立体选择性大于 β- NF组 .在对照组中代谢无立体选择性 ,且 Km,Vmax值均小于β- NF,Dex预处理组。结果提示 ,CYP1 A,CYP3A4亚族对普罗帕酮 (PPF)的 N-去丙基化有贡献 .(R/S) -The stereoselectivity of phase I metabolism of racemic propafenone(PPF) in vitro was investigated using chiral derivatization with GITC followed by RP HPLC analysis. The metabolite N depropylpropafenone was found in rat liver microsomes induced by dexamethasone(Dex) or β naphthoflavone (β NF), and racemic propa fenone undergoes stereoselective metabo lism at low concentration, but not at high concentration, with R(-) PPF priority in clearance. The K m of R(-) PPF is smaller than that of S(+) PPF, whereas the difference in V max is not significant. The degree of stereoselectivity in Dex pretreated group is larger than that in β NF pretreated group. In control group, no stereoselectivity was found. It is suggested that CYP1A and CYP3A4 contribute to PPF N dealkylation, which exhibits stereoselectivity depending on substrate concentration.

关 键 词：普罗帕酮 细胞色素P450 肝微粒体 抗心律失常药 

分 类 号：R963[医药卫生—微生物与生化药学]