本文選題：丁苯酞　切入點：藥物代謝　出處：《藥學(xué)學(xué)報》2015年05期 　論文類型：期刊論文

【摘要】：應(yīng)用大鼠/人肝微粒體體外孵育體系和大鼠體內(nèi)動物模型,鑒定了參與丁苯酞(NBP)代謝的主要CYP450同工酶,并評價了NBP對肝臟主要CYP450同工酶的誘導(dǎo)和抑制作用。大鼠(正常及誘導(dǎo))和人肝微粒體體外溫孵體系中加入CYP450同工酶選擇性抑制劑,通過測定NBP代謝速率的變化鑒定參與NBP代謝的CYP450同工酶。采用同工酶探針底物法評價不同濃度NBP對大鼠和人肝微粒6種主要CPY450同工酶的體外抑制作用;大鼠灌胃(160 mg·kg-1)和靜脈注射(20 mg·kg-1)NBP后評價NBP對大鼠肝臟主要同工酶的誘導(dǎo)和抑制作用。在加入大鼠CYP2C11、2E1、3A1/2和人CYP2C19、2E1、3A4/5的選擇性抑制劑后,NBP的代謝分別下降了38.8%、86.2%、78.4%和51.0%、92.0%、58.9%,而在CYP2E1和3A1/2高誘導(dǎo)的大鼠肝微粒體中NBP的代謝速率分別提高了25.5%和68.9%。當(dāng)NBP體外濃度達(dá)到200μmol·L-1時,對大鼠肝微粒體CYP1A2、2C6、2C11和2D2有一定抑制作用;NBP體外濃度達(dá)到15μmol·L-1時,對人肝微粒體CYP2C19有一定抑制作用。上述結(jié)果提示,大鼠CYP2E1、3A1/2和2C11以及人CYP2E1、3A4/5和2C19是參與NBP代謝的主要CYP450同工酶。體外較高濃度NBP對人CYP2C19有一定的抑制作用。大鼠連續(xù)灌胃或靜脈給予NBP,未觀察到NBP對肝微粒體CYP450主要同工酶存在顯著的誘導(dǎo)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.
【作者單位】： 中國醫(yī)學(xué)科學(xué)院&北京協(xié)和醫(yī)學(xué)院北京協(xié)和醫(yī)院臨床藥理研究中心&轉(zhuǎn)化醫(yī)學(xué)中心;中國醫(yī)學(xué)科學(xué)院藥物研究所創(chuàng)新藥物非臨床藥物代謝及藥代/藥效研究北京市重點實驗室;
【基金】：國家“十一五”重大新藥創(chuàng)制專項資助項目(2008ZX09312016) 國家“十二五”重大新藥創(chuàng)制專項資助項目(2012ZX09303006-002)
【分類號】：R96

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