采用重组人源 CYP酶研究艾瑞昔布的体外羟基化代谢-.docVIP

采用重组人源CYP 酶研究艾瑞昔布的体外羟基化代谢 李　强3 ,黄海华 13 ,董　宇2,钟大放 2 (沈阳药科大学1.微生物学教研室,2.药物代谢与药物动力学实验室,辽宁沈阳110016; 3.吉林大学生命科学学院,吉林长春130023 摘要:目的　探讨新型抗炎镇痛药艾瑞昔布在人体内的羟基化代谢酶。方法　用体外重组的人源细胞色素 P450(CYP 进行孵育代谢实验,液相色谱2多级质谱法分析代谢产物和残留的母体药物,利用整体归一化法对4种CYP 酶的代谢作用大小进行评估。结果　艾瑞昔布羟基化代谢可由CYP2C9,CYP2D6和CYP3A4催化,其各自作用 大小分别为6215%,2111%和1614%。结论　CYP2C9为艾瑞昔布羟基化的主要代谢酶。 关键词:细胞色素P450;羟基化代谢;艾瑞昔布;液相色谱2多级质谱法;整体归一化 中图分类号:R969.1;R969.2;Q559.9;R971.1　文献标识码:A 　文章编号:0513-4870(200505-0410-04 收稿日期:2004206218. 基金项目:国家高技术研究发展计划(863计划课题 (2003AA2Z347C . 3 通讯作者　Tel:86-243795,Fax:86-24 E 2mail:zhongdf@china .com I nvesti gati on on the hydroxyl ati on met abolis m of i m recoxi b in vitro by usi n g reco mbi n ant hu man CYPs L IQ iang 3 ,HUANG Hai 2hua 13 ,DONG Yu 2,ZHONG Da 2fang 2 (1.D epart m ent of Phar m aceutical M icrobiology, 2.L aboratory of D rug M etabolis m and Phar m acokinetics,Shenyang Phar m aceutical U niversity,Shenyang 110016,China; 3.College of L ife Science,J ilin U niversity,Changchun 130023,China Abstract:A i m 　T o identify the drug 2metabolizing enzy mes involved in the hydr oxylati on of the ne w anti 2infla mmat ory and anodyne i m recoxib .M ethods 　I m recoxib was incubated with heter ol ogous exp ressi on hu cyt ochr o me P450(r CYPs in vitro ,and metabolites and re mained parent drug were detected with liquid chr omat ography 2multistage mass s pectr ometry .The contributi on of 4CYPs in the hydr oxylati on metabolis m of i m recoxib was evaluated by t otal nor malized rate (T NR method .Results I m recoxib is metabolized by CYP2C9,CYP2D6and CYP3A4,with the rate of 6215%,2111%and 1614%,res pectively .Conclusi on 　CYP2C9is the maj or enzy me involved in i m recoxib hydr oxylati on metabolis m. Key words:cyt ochr ome P450;hydr oxylati on metabolis m;i m recoxib;liquid chr omat ography 2multistage mass s pectr ometry;t otal nor malized rate 　　艾瑞昔布(i m recoxib,图1为我国正在研制开发中的新药,环氧化酶22(COX 22特异性抑制剂,对因炎性介质引起的环氧化酶22的生成有较强抑制作用,进而发挥止痛及抗炎作用[1] 。研究表明,该药在人体内绝大部分以代谢物形式消除,主要代谢 途径是经肝脏代谢为4