【作者】 刘可； 钟大放； 袁涛； 李聃； 陈笑艳；

【Author】 LIU Ke,ZHONG Da-fang,YUAN Tao,LI Dan,CHEN Xiao-yan Shanghai Institute of Materia Medica,Chinese Academy of Sciences,646 Songtao Road,Shanghai 201203,China

【机构】 中国科学院上海药物研究所；

【摘要】 目的:研究多沙唑嗪人体内代谢过程的立体选择性。方法:采用手性LC-MS/MS法测定人血浆中多沙唑嗪对映体浓度,采用LC/MSn法鉴定多沙唑嗪对映体在人肝微粒体中的代谢产物,并对立体选择性的代谢途径进行酶动力学分析。结果:人口服4mg甲磺酸多沙唑嗪消旋体控释片后,S-（+）与R-（-）异构体AUC_0-t,C_max和CL的比值分别为2.3,2.1和0.43。在人肝微粒体中共鉴定出8中代谢产物,其中18位碳上羟基化代谢途径存在显著的立体选择性,S-（+）-和R-（-）-异构体在人肝微粒体中V_max分别为24.3和137.3 pmol/min/mg,K_m分别为13.8和16.5μM。结论:多沙唑嗪在人体内药代动力学过程存在高的立体选择性,体外代谢研究结果表明18位羟基化代谢途径为决定立体选择性代谢的关键。更多还原

【Abstract】 AIM:To study the stereoselective pharmacokinetics and metabolism of doxazosin in humans.METHODS:A sensitive enantioseletive LC-MS/MS method was developed and validated for determination of doxazosin in human plasma.The stereoselective metabolic pathways of doxazosin in liver microsome were investigated by LC/MSn method.RESULTS:The S-（+）/R-（-） ratios of C_max and AUC_0-t,were 2.1 and 2.3 after an oral administration of 4 mg racemic doxazosin mesylate controlled release tablet to two healthy volunteers.The clearance(CL_int) of 18-hydroxylation in human liver microsomes were 8.42 and 1.76μl/min/mg for R-（-）- and S- （+）-doxazosin,respectively.CONCLUSION:The pharmacokinetics of doxazosin in humans showed high stereoselectivity.The 18- hydroxy-doxazosin was the key factor in doxazosin stereoselective metabolism.更多还原