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首页> 外文期刊>Biochemical Pharmacology >P-glycoprotein deficiency enhances metabolic activation of and platelet response to clopidogrel through marked up-regulation of Cyp3a11 in mice: Direct evidence for the interplay between P-glycoprotein and Cyp3a
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P-glycoprotein deficiency enhances metabolic activation of and platelet response to clopidogrel through marked up-regulation of Cyp3a11 in mice: Direct evidence for the interplay between P-glycoprotein and Cyp3a

机译：P-糖蛋白缺乏通过标记为小鼠CYP3A11的上调来提高对氯吡格雷的代谢活化和血小板反应：P-糖蛋白和CYP3A之间相互作用的直接证据

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摘要

Variability in P-glycoprotein (P-gp) efflux transporting activity was supposed to be involved in altered intestinal absorption and bioavailability of clopidogrel in patients; however, reliable evidence is still lacking. In this study, we sought to determine whether P-gp could play an important role in the metabolic activation of and platelet response to clopidogrel in mice. Abcb1a/1b knock-out (KO) and wild-type (WT) mice were used to evaluate differences in the intracellular accumulation of clopidogrel in the intestine, liver, and brain tissues and in systemic exposure of clopidogrel and its main metabolites as well as the mechanisms involved. Results indicated that, compared with WT mice, KO mice exhibited an 84% increase in systemic exposure of clopidogrel active thiol metabolite H4 and a 14.5% rise of suppression of ADP-induced platelet integrin alpha IIb beta 3 activation, paralleled by a 41% decrease in systemic exposure of clopidogrel due to enhanced systemic clearance. Furthermore, KO mice displayed a 45% increase in Cyp3a11 but a 23% decrease in Ces1 at their protein levels compared with WT mice. Concurrently, intracellular clopidogrel concentrations in the tissues examined did not differ significantly between KO and WT mice. We conclude that although P-gp does not transport clopidogrel and its major metabolites in mice, P-gp-deficient mice exhibit elevated formation of the active metabolite H4 and enhanced antiplatelet effect of clopidogrel through up-regulation of Cyp3a11 and down-regulation of Ces1, suggesting that P-gp activity may correlate inversely with the formation of H4 and antiplatelet efficacy of clopidogrel in clinical settings due to P-gp and CYP3A4 interplay.
机译：p-糖蛋白（p-gp）流出转运活性的可变性应该参与患者氯吡格雷的改变的肠道吸收和生物利用度;但是，可靠的证据仍然缺乏。在这项研究中，我们试图确定P-GP是否可以在对小鼠氯吡格雷的代谢激活和血小板反应中发挥重要作用。 ABCB1A / 1B敲除（KO）和野生型（WT）小鼠用于评估肠，肝病和脑组织中氯吡格雷的细胞内积累以及氯吡格雷的全身暴露以及其主要代谢物以及其主要代谢物的差异以及涉及的机制。结果表明，与WT小鼠相比，KO小鼠在氯吡格雷氏菌属活性硫醇代谢物H4的全身暴露增加84％，ADP诱导的血小板整合蛋白α3活化的14.5％抑制抑制，并联降低41％氯吡格雷的全身暴露于增强的全身间隙。此外，KO小鼠展示了CYP3A11增加了45％，但与WT小鼠相比，CES1的CES1减少了23％。同时，在KO和WT小鼠之间检查的组织中的细胞内氯吡格雷浓度没有显着差异。我们得出结论，尽管P-GP不将氯吡格雷运输及其主要代谢产物，但P-GP缺陷小鼠表现出升高的形成活性代谢物H4，并通过CYP3A11的上调和CES的下调增强氯吡格雷的抗血小板效果。据表明，由于P-GP和CYP3A4相互作用，P-GP活性可能与氯吡格雷的H4和抗血小板的形成和抗血小板效能相相关。

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  • 来源
    《Biochemical Pharmacology》 |2021年第1期|共11页
  • 作者

    Ji Jin-Zi; Li Yi-Fei; Jiang Li-Ping; Tai Ting; Ge Peng-Xin; Mi Qiong-Yu; Zhu Ting; Xie Hong-Guang;

  • 作者单位

    Nanjing Med Univ Nanjing Hosp 1 Div Clin Pharmacol Gen Clin Res Ctr Nanjing 210006 Peoples R;

    Nanjing Med Univ Nanjing Hosp 1 Div Clin Pharmacol Gen Clin Res Ctr Nanjing 210006 Peoples R;

    Nanjing Med Univ Nanjing Hosp 1 Div Clin Pharmacol Gen Clin Res Ctr Nanjing 210006 Peoples R;

    Nanjing Med Univ Nanjing Hosp 1 Div Clin Pharmacol Gen Clin Res Ctr Nanjing 210006 Peoples R;

    China Pharmaceut Univ Dept Clin Pharm Coll Basic Med &

    Clin Pharm Nanjing 211198 Peoples R China;

    Nanjing Med Univ Nanjing Hosp 1 Div Clin Pharmacol Gen Clin Res Ctr Nanjing 210006 Peoples R;

    China Pharmaceut Univ Dept Clin Pharm Coll Basic Med &

    Clin Pharm Nanjing 211198 Peoples R China;

    Nanjing Med Univ Nanjing Hosp 1 Div Clin Pharmacol Gen Clin Res Ctr Nanjing 210006 Peoples R;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药理学;
  • 关键词

    ABCB1; Carboxylesterase 1; Clopidogrel; Cyp3a; Metabolism; P-glycoprotein;

    机译：ABCB1;羧基酯酶1;氯吡格雷;CYP3A;新陈代谢;p-糖蛋白;

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