10,11-二氢-10-羟基卡马西平在不同种属肝微粒体中经UGT酶代谢的差异性研究  

The Metabolism of 10,11-Dihydro-10-hydroxycarbamazepine via UGTEnzymes in Liver Microsomes of Different Species

作　　者：黄凯[1] 刘鑫[2] 刘志浩[3] 赵曼曼[4] 宋俊科[4] 霍记平[5] 

机构地区：[1]南京医科大学附属无锡市人民医院,江苏无锡214013 [2]中国医学科学院北京协和医学院北京协和医院药剂科,北京100730 [3]大连医科大学药学院临床药理教研室,辽宁大连116044 [4]中国医学科学院北京协和医学院药物研究所,北京100050 [5]首都医科大学附属北京天坛医院药学部,北京100050

出　　处：《药品评价》2017年第14期13-18,共6页Drug Evaluation

基　　金：奥卡西平对癫痫儿童血清Hcy和AMDA影响的研究。无锡市医院管理中心面上基金项目;编号:YGZXM1512

摘　　要：目的:研究10,11-二氢-10-羟基卡马西平(Monoh ydroxycar bazepine,MHD)在不同种属肝微粒体中经尿苷二磷酸葡萄糖醛酸基转移酶(UDP-glucuronosyltransferase,UGT)代谢的差异性。方法:建立10,11-二氢-10-羟基卡马西平-O-β-葡萄糖醛酸结合物(MHD-G)的HPLC-MS/MS检测方法;采用肝微粒体体外孵育法观察MHD在大鼠、犬、猴、人肝微粒体中的代谢稳定性;分析各种属肝微粒体中MHD-G的生成量,并比较各动力学参数的差异性。结果:MHD-G在5~4 000 ng·m L^(-1) 呈良好的线性关系,满足检测要求;MHD在大鼠、犬、猴、人肝微粒体中均可生成MHD-G,但MHD与肝微粒体UGT的Km值排序:猴>人>大鼠>犬;最大反应速率排序:猴>犬>大鼠>人;内在清除率排序:犬>大鼠>猴>人。结论:MHD在不同种属肝微粒体中的UGT代谢动力学性质存在一定的差异。Objective:The present study aims to compare the metabolism differences of10,11-Dihydro-10-hydroxycarbamazepine(MHD)mediated by UDP-glucuronosyltransferase(UGT)in liver microsomes of rat,dog,monkey and human.Methods:A sensitive HPLC-MS/MS method was developed for the quantitation of10,11-Dihydro-10-hydroxycarbamazepine-O-β-glucuronide(MHD-G),and the metabolic stability of MHD in rat liver microsome(RLM),dog liver microsome(DLM),monkey liver microsome(MLM)and human liver microsome(HLM)was investigated using liver microsomes incubation.The concentration of MHD-G in incubates was determined and kinetic parameters were compared in four species.Results:The calibration curve was linear over the range5-4000ng·mL-1for MHD-G,which was sufficient for enzyme kinetic studies.MHD-G could be determined in RLM,DLM,MLM and HLM,respectively.In addition,the rank order of Km for MHD glucuronidation was MLM>HLM>RLM>DLM;Vmax:MLM>DLM>RLM>HLM;CLint:DLM>RLM>MLM>HLM.Conclusions:Species differences of UGT metabolic characteristics of MHD were existed in four liver microsomes.

关 键 词：奥卡西平 10 11-二氢-10-羟基卡马西平 肝微粒体 尿苷二磷酸葡萄糖醛酸基转移酶 

分 类 号：R96[医药卫生—药理学]