中文摘要：

目的通过亚细胞、器官和整体动物3种水平的代谢实验,研究了利福布汀（rifabutin,RBT）自身代谢以及RBT被连续给药后对自身代谢及肝细胞色素P450酶系的影响,为临床的合理用药提供有益的指导。方法36只W istar大鼠随机分为6组,每组6只。3种水平的实验研究各有空白对照组和RBT给药组（口服灌胃300 mg·kg^-1·d^-1×7 d）。亚细胞代谢研究利用制备的肝微粒体,体外温孵CYP1A2,CYP2D6,CYP2C9,CYP2E1及CYP3A等几种重要亚酶的特异性底物,通过比较其代谢产物的生成速率来评价RBT对这些亚酶的影响;器官代谢研究采用大鼠原位肝脏灌流方法,整体实验动物代谢研究通过颈静脉插管手术,器官与整体代谢都是比较其代谢参数的差异。结果连续口服7 d RBT之后,酶蛋白水平和总体CYP450活力分别为空白对照组的84.60%和410.0%。CYP3A及CYP2D6亚酶活性分别为空白对照组的184.0%及155.7%。器官和整体动物水平都表明RBT连续给药组显著加快了自身药物的代谢,t1/2分别为空白对照组的58.96%和71.00%,并且器官水平显示AUC也仅为空白对照组的49.06%。结论RBT代谢存在自身诱导,连续服用RBT之后,不仅自身的代谢将会被改变,那些经CYP3A及CYPD2D6代谢的合用药物的代谢也将被改变。

英文摘要：

OBJECTIVE Evaluate effect of rifabutin on itself metabolism and some main CYP450 isoenzymes in subcelluar,organic and in vivo studies for guiding drugs administration in clinical.METHODS 36 Rats were divided into 6 groups at random,n=6 in every group.There were the control group and the rifabutin taken group（300 mg·kg^-1,po,7 d） in 3 different kinds of studies.In the subcellular studies,we incubated the specific substrates using the prepared microsome,and then compared the form rate of their metabolites to evaluate the main isoform activity,such as CYP1A2,CYP2D6,CYP2C9,CYP2E1 and CYP3A.The liver perfusion and jugular intubatton（blood was sampled in different time next day）were applied in the organic studies and in vivo studies respectively,and then compared the metabolism parameters of rifabutin.RESULTS Protein concentration and the enzyme activities turned to 84.60% and 410.0% comparing the control group respectively.CYP3A and CYP2D6 activities turn to 84.00% and 155.7% comparing the control group,respectively.The metabolism of rifabutin was enhanced in rifabutin taken group both organic and in vivo studies.t1/2 were turned to 58.96% and 71.00% respectively and AUC was turned to 49.06% comparing the control group in organic level.CONCLUSION There was autoinduction in the metabolism of rifabutin.The metabolism of not only rifabutin itself but also those drugs metabolized by CYP3A or CYP2D6 would be increased after pretreatment of rifabutin.