他克莫司在溃疡性结肠炎模型大鼠肝微粒体中的代谢研究  

Metabolism of FK506 in hepatic microsomes of rats with ulcerative colitis

作　　者：吴衡 刘云娣[1] 李雪 苏金和[1] WU Heng;LIU Yun-di;LI Xue;SU Jin-he(The First Affiliated Hospital of Guangzhou University of Chinese Medicine,Guangzhou 510405;Air Force Hospital of Southern Theater Command of the People’s Liberation Army,Guangzhou 510602)

机构地区：[1]广州中医药大学第一附属医院,广州510405 [2]南部战区空军医院,广州510602

出　　处：《中南药学》2020年第9期1494-1498,共5页Central South Pharmacy

摘　　要：目的考察葡聚糖硫酸钠(DSS)诱导的溃疡性结肠炎(UC)模型大鼠肝微粒体对他克莫司(FK506)的代谢影响以及其代谢酶表达变化。方法给予大鼠5%DSS溶液连续自由饮用7 d,诱导UC模型,制备正常和模型大鼠肝微粒体。用不同浓度的FK506与肝微粒体共孵育,用LC/MS/MS检测孵育体系中FK506的代谢产物13-DMT的生成量,对比FK506在正常和模型大鼠肝微粒体中的代谢差异,同时采用Western blot方法检测肝脏中CYP3A1的表达水平。结果经DSS诱导后,模型组大鼠表现出明显的UC症状。FK506在大鼠肝微粒体中的代谢方式符合米氏方程。与正常组比较,FK506在模型组肝微粒体中的代谢速率下降了25.3%,Km值增加了36.4%,差异具有统计学意义(P<0.001)。同时模型组肝脏中CYP3A1的表达较正常组下降,差异具有统计学意义(P<0.05)。结论FK506在肝微粒体中代谢会受到UC的影响而改变,这可能与其主要代谢酶CYP3A1的活性改变有关,提示我们UC状态可能会影响FK506在患者体内的药动学。Objective To determine the change in metabolic behaviors and enzymes of tacrolimus(FK506)in hepatic microsomes from ulcerative colitis(UC)model rats induced by sodium glucan sulfate(DSS).Methods The UC rats model rats were induced by 5%DSS free drinking for 7 days.Then the normal and model rat hepatic microsomes were prepared simultaneously.The different concentrations of FK506 were coincubated with the microsomes,and the amount formation of the metabolite 13-DMT was detected by LC/MS/MS.The metabolizing activities of FK506 and the expression level of CYP3A1 in microsomes were compared between the normal and the model group.Results After DSS induction,the model group showed typical symptoms of UC.The metabolic behaviors of FK506 in rat hepatic microsomes conformed to the typical Michaelis-Menten kinetics.Compared with the normal group,the Vmax of FK506 in the model group decreased by 25.3%and the Km increased by 36.4%(P<0.001).Meanwhile,the expression of CYP3A1 in the model group significantly decreased as compared with that of the normal group(P<0.05).Conclusion The metabolism of FK506 in hepatic microsomes can be changed by UC,which may be related to the change of CYP3A1 activity,it suggesting UC may affect the pharmacokinetics of FK506.

关 键 词：他克莫司 溃疡性结肠炎 CYP3A酶 肝微粒体 药物代谢 

分 类 号：R965[医药卫生—药理学]