丁苯酞与大鼠和人肝CYP450同工酶的相互作用

发布时间：2018-03-17 16:26

本文选题：丁苯酞　切入点：药物代谢　出处：《药学学报》2015年05期 　论文类型：期刊论文

【摘要】：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。
[Abstract]:The main CYP450 isozymes involved in the metabolism of butylphthalide were identified by using rat / human liver microsomal incubation system and animal model in vivo. The effects of NBP on the induction and inhibition of major CYP450 isozymes in the liver were evaluated. The selective inhibitor of CYP450 isozyme was added to rat (normal and induced) and human liver microsomes in vitro incubation system. The CYP450 isozymes involved in NBP metabolism were identified by measuring the metabolic rate of NBP. The inhibitory effects of different concentrations of NBP on six major CPY450 isozymes of rat and human liver particles were evaluated by using isozyme probe substrate method. The induction and inhibition effect of NBP on the main isozymes of rat liver were evaluated after intragastric administration of 160mg 路kg-1) and 20 mg 路kg-1)NBP. The metabolism of NBP decreased 38.86.2mg 路kg-1 / 2 in CYP2E1 and 58.98.9in CYP2E1 and 3A1a / 2 in 3A1a / 2 in rats, respectively, after adding the selective inhibitors of CYP2C112E1E1A4A4 / 2 and human CYP2C19C19E1E1O3A4 / 5. The metabolic rate of NBP in rat liver microsomes was increased by 25.5% and 68.9, respectively, when the concentration of NBP in vitro reached 200 渭 mol 路L -1. The inhibitory effect of NBP on rat liver microsomal CYP1A2C6C11 and 2D2 in vitro was 15 渭 mol 路L ~ (-1). These results suggest that, when the concentration of NBP in vitro reaches 15 渭 mol 路L ~ (-1), it has a certain inhibitory effect on human liver microsomal CYP2C19. Rat CYP2E1T3A1 / 2 and 2C11 and human CYP2E1A3A4 / 5 and 2C19 are the main CYP450 isozymes involved in the metabolism of NBP. High concentration of NBP in vitro has a certain inhibitory effect on human CYP2C19. It is not observed that NBP has the same effect on liver microsomal CYP450 after continuous gastric administration or intravenous administration in rats. The inducement and inhibition of the enzyme were significant.
【作者单位】：中国医学科学院&北京协和医学院北京协和医院临床药理研究中心&转化医学中心;中国医学科学院药物研究所创新药物非临床药物代谢及药代/药效研究北京市重点实验室;
【基金】：国家“十一五”重大新药创制专项资助项目(2008ZX09312016) 国家“十二五”重大新药创制专项资助项目(2012ZX09303006-002)
【分类号】：R96

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