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应用大鼠/人肝微粒体体外孵育体系和大鼠体内动物模型,鉴定了参与丁苯酞(NBP)代谢的主要CYP450同工酶,并评价了NBP对肝脏主要CYP450同工酶的诱导和抑制作用。大鼠(正常及诱导)和人肝微粒体体外温孵体系中加入CYP450同工酶选择性抑制剂,通过测定NBP代谢速率的变化鉴定参与NBP代谢的CYP450同工酶。采用同工酶探针底物法评价不同浓度NBP对大鼠和人肝微粒6种主要CPY450同工酶的体外抑制作用;大鼠灌胃(160 mg·kg-1)和静脉注射(20 mg·kg-1)NBP后评价NBP对大鼠肝脏主要同工酶的诱导和抑制作用。在加入大鼠CYP2C11、2E1、3A1/2和人CYP2C19、2E1、3A4/5的选择性抑制剂后,NBP的代谢分别下降了38.8%、86.2%、78.4%和51.0%、92.0%、58.9%,而在CYP2E1和3A1/2高诱导的大鼠肝微粒体中NBP的代谢速率分别提高了25.5%和68.9%。当NBP体外浓度达到200μmol·L-1时,对大鼠肝微粒体CYP1A2、2C6、2C11和2D2有一定抑制作用;NBP体外浓度达到15μmol·L-1时,对人肝微粒体CYP2C19有一定抑制作用。上述结果提示,大鼠CYP2E1、3A1/2和2C11以及人CYP2E1、3A4/5和2C19是参与NBP代谢的主要CYP450同工酶。体外较高浓度NBP对人CYP2C19有一定的抑制作用。大鼠连续灌胃或静脉给予NBP,未观察到NBP对肝微粒体CYP450主要同工酶存在显著的诱导和抑制作用。
The major CYP450 isoenzymes involved in the metabolism of butylphthalide (NBP) were identified using in vitro rat / human liver microsomal in vitro and rat in vivo models and the induction and inhibition of NBP on the major CYP450 isoenzymes in the liver were evaluated effect. CYP450 isoenzyme inhibitor was added to rat (normal and induced) and human liver microsomes in vitro, and the CYP450 isoenzymes involved in NBP metabolism were identified by measuring changes in NBP metabolic rate. The isoenzyme probe substrate method was used to evaluate the inhibitory effects of NBP on six major CPY450 isoenzymes in rats and human liver particles. The intragastric administration of 160 mg · kg -1 and intravenous injection of 20 mg · Kg-1) NBP was used to evaluate the induction and inhibition of major isoenzymes in rat liver by NBP. NBP metabolism decreased by 38.8%, 86.2%, 78.4% and 51.0%, 92.0% and 58.9% respectively after the addition of selective inhibitors of CYP2C11, 2E1, 3A1 / 2 and CYP2C19, 2E1 and 3A4 / , While the metabolic rate of NBP increased by 25.5% and 68.9% in CYP2E1 and 3A1 / 2 highly induced rat liver microsomes, respectively. When the concentration of NBP reached 200μmol·L-1, the inhibitory effect on CYP1A2, 2C6, 2C11 and 2D2 of rat liver microsome was inhibited. When NBP reached 15μmol·L-1 in vitro, it inhibited CYP2C19 of human liver microsome effect. The above results suggest that the rat CYP2E1, 3A1 / 2 and 2C11 as well as human CYP2E1, 3A4 / 5 and 2C19 are the major CYP450 isoenzymes involved in NBP metabolism. In vitro, higher concentrations of NBP on human CYP2C19 have a certain inhibitory effect. NBP was administered intragastrically or intravenously in rats, and no significant induction and inhibition of CYP450 major isoforms by NBP were observed.