中国人肝微粒体体外代谢奥美拉唑的酶促反应动力学  

ENZYME KINETIC STUDIES ON THE IN VITRO METABOLISM OF OMEPRAZOLE BY CHINESE HUMAN LIVER MICROSOMES

作　　者：赵莉[1] 楼雅卿[1] 

机构地区：[1]北京医科大学药理系

出　　处：《药学学报》1996年第5期352-357,共6页Acta Pharmaceutica Sinica

摘　　要：采用中国成人肝微粒体建立了体外孵育代谢奥美拉唑的酶促反应，应用反相ＨＰＬＣ法测定孵育体系中奥美拉唑的两种主要代谢物——羟奥美拉唑和奥美拉唑砜的含量。该方法灵敏度高、简便、快速、可靠。实验结果表明，人肝微粒体主要通过羟化和Ｓ原子氧化代谢奥美拉唑。其羟化反应的最大反应速率（Ｖｍａｘ）和米氏常数（Ｋｍ）分别为４２．９０ｎｍｏｌ·ｍｉｎ￣（－１）·ｍｇ￣（－１）和６．４９μｍｏｌ·Ｌ￣（－１），而Ｓ原子氧化代谢为６．６３ｎｍｏｌ·ｍｉｎ￣（－１）·ｍｇ￣（－１）和１１．８０μｍｏｌ·Ｌ￣（－１）。消旋美芬妥英、地西泮、去甲西泮及罂粟碱对奥美拉唑体外代谢的实验结果表明，上述药物对奥美拉唑的羟化代谢均有不同程度的抑制作用，其中美芬妥英、地西泮、去甲西泮为奥美拉唑羟化代谢的竞争性抑制剂，罂粟碱为反竞争性抑制剂。同时，这４种药物对奥美拉唑的Ｓ原子氧化代谢亦有一定的影响。In the present study,a specific and reliable method was developed for thedetermination of omeprazole and its two major metabolites:hydroxyomeprazole(OH -OPZ)andomeprazole sulfone(OPZ-SFN)in Chinese adult human liver microsome by reversed phase HPLCassay. Formation of these metabolites is linear for at least 60 min and between 0.25 and 1mg· ml-1of microsomal protein. The enzyme kinetic analysis of the reaction revealed that the hydroxylationVmax and Km obtained with the human liver microsomal preparation were 42.9 nmol· min-1·(mgprotein)-1 and 6.49μmol·L-1,respectively.The maximum formation rates of OPZ-SFN(Vmax)was 6.63 nmol· min-1·(mg protein)-1, with a Km value of 11.8μmol·L-1. A number ofcompounds were tested for their ability to inhibit OPZ metabolism, Our results showed thatmephenytoin,diazepam and nordiazepam are competitive inhibitors and papaverine is an uncompetitiveinhibitor of OPZ hydroxylation, These studies suggest that the same isozyme metabolising MP,DZ andNDZ(may be P450 2C or P450 3A) may be involved in the hydroxylation of OPZ,Moreover,thecompounds tested also have some effects on the for mation of OPZ-SFN in vitro with Chinese humanliver microsomes.

关 键 词：肝微粒体 奥美拉唑 羟奥美拉唑 酶促反应 

分 类 号：R975.6[医药卫生—药品]