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首页> 外文期刊>Biochemical Pharmacology >Cytochrome P450 3A selectively affects the pharmacokinetic interaction between erlotinib and docetaxel in rats
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Cytochrome P450 3A selectively affects the pharmacokinetic interaction between erlotinib and docetaxel in rats

机译：细胞色素p450 3a选择性地影响厄洛替尼和多西紫杉醇在大鼠之间的药代动力学相互作用

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摘要

Erlotinib as a first-line drug is used in non-small cell lung cancer (NSCLC) patients with sensitive EGFR mutations, while resistance to this drug will occur after several years of treatment. Therefore, the micro tubule disturber docetaxel is introduced as combined regimen in clinical trials. This report investigated the potentials and mechanisms of drug-drug interaction (DDI) between erlotinib and docetaxel using wild type (WT) and Cyp3a1/2 knockout (KO) rats. The erlotinib O-demethylation and docetaxel hydroxylation reactions in the absence or the presence of another drug were analyzed in vitro via the assay of rat liver microsomes. In whole animal studies, erlotinib and docetaxel were given to WT and KO rats individually or jointly, and the pharmacokinetic profiles of these two drugs were analyzed and compared among different groups. The results showed that docetaxel not only inhibited the CYP3A-mediated biotransformation of erlotinib in vitro, but also significantly increased the maximum concentration and systemic exposure of erlotinib in vivo in WT rats. In contrast, the DDI was significantly attenuated in KO rats. On the other hand, erlotinib did not influence docetaxel either in vitro biotransformation or in vivo pharmacokinetic behaviors. These results exhibited the potentials of erlotinib-docetaxel interaction and indicated that the CYP3A played the perpetrating role of docetaxel on erlotinib in rats. A better understanding of this DDI with CYP3A may help the regulation of the use of these two drugs, avoid potential problems, and adjust dose carefully and early in clinic. (C) 2017 Elsevier Inc. All rights reserved.
机译：作为一线药物的Erlotinib用于非小细胞肺癌（NSCLC）敏感EGFR突变患者，而在几年的治疗后将发生对该药物的抵抗力。因此，在临床试验中引入微管助剂多西紫杉醇。本报告调查了使用野生型（WT）和CYP3A1 / 2敲除（KO）大鼠的厄洛替尼和多西紫杉醇之间的药物 - 药物相互作用（DDI）的潜在和机制。通过大鼠肝微粒体的测定，体外分析在不存在或存在另一种药物中的厄洛替尼O-去甲基化和多西紫杉醇羟基化反应。在整个动物研究中，单独或共同给予WT和KO大鼠的Erlotinib和多西紫杉醇，并分析了这两种药物的药代动力学谱并在不同的组中进行比较。结果表明，多西紫杉醇不仅抑制了在体外厄洛替尼的CYP3A介导的生物转化，而且显着提高了在WT大鼠中体内体内Erlotinib的最大浓度和全身暴露。相比之下，DDI在KO大鼠中显着减弱。另一方面，厄洛替尼没有影响多西紫杉醇，无论是体外生物转化还是体内药代动力学行为。这些结果表现出厄洛替尼 - 多西紫杉醇相互作用的潜力，并表明CYP3A在大鼠中发挥了多西紫杉醇对厄洛替尼的作用。更好地了解与CYP3A的DDI有助于调节使用这两种药物，避免潜在的问题，并在临床诊所和早期调整剂量。 （c）2017年Elsevier Inc.保留所有权利。

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  • 来源
    《Biochemical Pharmacology》 |2017年第2017期|共11页
  • 作者

    Qin Xuan; Lu Jian; Wang Peili; Xu Peipei; Liu Mingyao; Wang Xin;

  • 作者单位

    East China Normal Univ Shanghai Key Lab Regulatory Biol Inst Biomed Sci Shanghai Peoples R China;

    East China Normal Univ Shanghai Key Lab Regulatory Biol Inst Biomed Sci Shanghai Peoples R China;

    East China Normal Univ Shanghai Key Lab Regulatory Biol Inst Biomed Sci Shanghai Peoples R China;

    East China Normal Univ Shanghai Key Lab Regulatory Biol Inst Biomed Sci Shanghai Peoples R China;

    East China Normal Univ Shanghai Key Lab Regulatory Biol Inst Biomed Sci Shanghai Peoples R China;

    East China Normal Univ Shanghai Key Lab Regulatory Biol Inst Biomed Sci Shanghai Peoples R China;

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

    Non-small cell lung cancer (NSCLC); Erlotinib; Docetaxel; Cyp3a1/2 KO rats; Drug-drug interaction;

    机译：非小细胞肺癌（NSCLC）;Erlotinib;多西紫杉醇;CYP3A1 / 2 KO大鼠;药物 - 药物相互作用;

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