地尔硫抑制大鼠肝脏药物代谢的机制  

Study on the mechanism involved in the inhibitory effect of diltiazem on the hepatic drug metabolism

作　　者：印绮平[1] 王宏图[1] 张静华[1] 奚念朱 

机构地区：[1]上海医科大学华山医院临床药学研究室,上海200040 [2]药学院生物药剂研究室,上海200032

出　　处：《中国临床药学杂志》1999年第2期100-100,共1页Chinese Journal of Clinical Pharmacy

摘　　要：目的:研究地尔硫(艹卓)(DZ)抑制大鼠肝脏药物代谢的机制.方法:(1)SD大鼠未诱导或经地塞米松(DEX)、苯巴比妥(PB)、β萘黄酮(BNF)诱导,制备肝微粒体,于DZ体外37℃温孵25min,检测细胞色素P450-Fe(Ⅱ)-代谢物(MI)复合物.(2)未诱导大鼠ip DZ 100mg/kg 3d,或经DEX诱导再给予单剂量DZ 100mg/kg,制备肝微粒体并检测MI复合物.结果:DEX、PB诱导组在体外分别有30.62%和10.30%MI复合物形成.未诱导大鼠ip DZ 3d,体内检测到7.9%MI复合物;经DEX诱导再给予单剂量DZ的大鼠,体内有17.57%MI复合物形成.结论:DZ在大鼠肝脏中经细胞色素P450 3A催化,发生N-去甲基化,生成的活性代谢物可与P450 3A络合而形成MI复合物,使P450 3A丧失部分活性.AIM:To investigate the mechanism involved in the inhibitory effect of diltia-zem (DZ) on hepatic drug metabolism. METHODS: (1)SD rats were untreated or treated with various inducers including dexamethasone(100 mg/kg,ig × 3d) ,phenobarbital (80 mg/ kg,ip　×　3d) and β-naphthoflavone(80 mg/kg,ig　× 3d). Liver microsomes were obtained from these rats and incubatd with DZ in the presence of reduced form of nicotinamide-adenine di-nucleotide phosphate. (2) SD rats were pretreated with dexamethasone for 3d and given a single dose of 100 mg/kg DZ, or were given three daily administration of DZ. Liver micro-somes were prepared for detecting P450-iron-metabolite (MI) complex absorbing around 455nm. RESULTS: Dexamethasone-treated and phenobarbital-treated rat microsomes gave some formation of MI complex, with the amount of 30.62% and 10. 30% respectively. A single dose of DZ to rats pretreated with dexamethasone gave rise to 17. 57% formation of MI complex. Three daily administration of DZ produced 7. 91% formation of MI complex.CONCLUSION:Both in vitro and in vivo studies suggest that DZ could be able to form com-plex with cytochrom P4503A during its N-demethylated metabolism in rat liver catalyzed by P4503A. And thus P4503A is inactivated by DZ.

关 键 词：地尔硫ZHUO 肝脏代谢 药物代谢 

分 类 号：R972[医药卫生—药品] R969.1[医药卫生—药学]