应用中国成人肝微粒体研究地西泮代谢  

Metabolism of diazepam in Chinese adult liver microsomes

作　　者：匡唐永[1] 楼雅卿[1] 

机构地区：[1]北京医科大学药理教研室

出　　处：《中国药理学与毒理学杂志》1995年第2期81-86,共6页Chinese Journal of Pharmacology and Toxicology

摘　　要：本文建立了中国成人肝库，并应用中国成人肝微粒体研究了中国人地西泮代谢的规律和代谢地西泮的肝微粒体细胞色素Ｐ４５０氧化酶的特点，结果表明，中国人的地西泮代谢主要经Ｎ－去甲基化和Ｃ３－羟化反应，分别生成去甲地西泮（ＮＤＺ）和羟地西拌（ＴＭＺ）两种代谢产物，随着底物浓度的增加，这两种酶促反应呈双曲线分布，当底物浓度＞２０μｍｏｌ·Ｌ－１时，Ｎ－去甲基化反应的速率低于羟化反应速率，羟地西泮代谢物生成量明显高于去甲地西泮，同时发现，中国成人肝微粒体中可能存在着两种与地西泮具有不同亲和力的药酶组份，结果还表明，异喹胍，奎尼丁（被Ｐ４５０２Ｄ６酶所催化代谢）和美芬妥因，苯妥英（被Ｐ４５０２Ｃ类酶所催化代谢）对中国人肝微粒体试管内地西泮代谢无影响，而普奈洛尔及与Ｓ－美芬妥英羟化代谢相关的奥米拉唑能显著地抑制试管内地西泮的Ｎ－去甲基化和Ｃ３－羟化代谢反应。催眠药甲喹酮能显著地激活地西泮的氧化代谢反应。By using Chinese adult liver samples. themetabolism of diazepam was studied in the Chinese livermicrosomes. The studies show that nordiazepam andtemazepam are the major products of diazepam metabolism.There are a high-affinity component and a low-affinity com-ponent of the enzymes for each metabolic pathway ofdiazepam. With the substrate in pmol. Lconcentration em-ployed in studies in vitro, the metabolism of diazepam may bemediated primarily by forms of cytochrome P450 with lowKn and high Vmax characteristics. Debrisoquine, quinidine,mephenytoin, phenytoin all had no significant effects ondiazepam metabolism in vitro in Chinese liver microsomes, in-dicating that diazcpam metabolism may not cosegregate withdebrisoquine or Smephenytoin polymorphic hydroxylationin Chinese subXcts. But omeprazole, whose metabolismcosegregates with that of Smephenytoin in both Chinese andCaucasian, and propranolol, whose elimination is related tothe polymorphic metabolisms of hoth debrisoquine andSmephenytoin, could competitively or noncornpetitively in-hibit the N-demethylation and C3-hydroxylation ofdiazepam. On the contrary, methaqualone could activate boththe metabolic pathways of diazepam in Chinese livermicrosomes.

关 键 词：地西泮 肝微粒体 美芬妥英 异喹胍 药物代谢 

分 类 号：R971.3[医药卫生—药品] R969.1[医药卫生—药学]