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首页> 外文期刊>RSC Advances >Reactive intermediates in naquotinib metabolism identified by liquid chromatography-tandem mass spectrometry: phase I metabolic profiling
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Reactive intermediates in naquotinib metabolism identified by liquid chromatography-tandem mass spectrometry: phase I metabolic profiling

机译：通过液相色谱 - 串联质谱法鉴定的Naquotinib代谢的反应性中间体：I相电子代谢分析

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Tyrosine kinase inhibitors (TKIs) are very efficient for the treatment of EGFR-mutated lung cancer and show improved therapeutic efficacy. However, treatment with both first- and second-generation TKIs results in acquired resistance and is related to various toxicities; the EGFR T790M mutation has been associated with this resistance. Naquotinib (ASP8273, NQT) is a novel third-generation epidermal growth factor receptor tyrosine kinase inhibitor that has been shown to be more potent than osimertinib in the management of L858R plus T790M mutations. However, its bioactivation may occur and promote the formation of reactive electrophiles that are toxic. We hypothesize that these reactive intermediates are potentially involved in the side effects of NQT. Reactive metabolites are often formed by phase I metabolic reactions and cannot be characterized directly as they are transient in nature. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we screened for in vitro metabolites of NQT formed during incubation with human liver microsomes and evaluated the generation of reactive electrophiles using capturing agents, such as methoxyamine and potassium cyanide, as nucleophiles that form stable adducts for identification by LC-MS/MS. Eight NQT phase I metabolites were found that had been formed by N-demethylation, oxidation, hydroxylation, and reduction. In addition, three reactive electrophiles, two aldehydes, and one iminium ion were identified, and the corresponding bioactivation mechanisms were proposed. The reported side effects of NQT may be related to the generation of reactive metabolites. Based on a literature review, this may be the first study of in vitro phase I metabolites, detailed structural characterizations, and NQT reactive intermediates.
机译：酪氨酸激酶抑制剂（TKIS）非常有效地治疗EGFR突变肺癌并显示出改善的治疗效果。然而，用第一代和第二代TKI的治疗导致获得性抗性并且与各种毒性有关; EGFR T790M突变与这种阻力有关。 Naquotinib（ASP8273，NQT）是一种新型的第三代表皮生长因子受体酪氨酸激酶抑制剂，其在L858R加上T790M突变的管理中已经显示出比Osimertinib更有效。然而，它的生物活化可能会发生并促进有毒的反应性电子手术的形成。我们假设这些反应性中间体可能涉及NQT的副作用。反应性代谢物通常通过代谢代谢反应形成，不能直接表征，因为它们是瞬态的。使用液相色谱 - 串联质谱（LC-MS / MS），我们筛选在与人肝微粒体温育期间形成的NQT体外代谢物，并使用捕获剂（例如甲氧胺和氰化钾）为亲核试剂评价反应性电子手机的产生形成稳定的加合物，用于通过LC-MS / MS鉴定。发现八个NQT期I代谢物已通过N-去甲基化，氧化，羟基化和还原形成。另外，鉴定了三种反应式电泳，两种反应性电泳和一个亚氨基离子，并提出了相应的生物活化机制。据报道的NQT的副作用可能与反应性代谢物的产生有关。基于文献综述，这可能是对体外I期代谢物，详细的结构表征和NQT反应性中间体的第一次研究。

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  • 来源
    《RSC Advances》 |2019年第18期|共15页
  • 作者

    Attwa Mohamed W.; Kadi Adnan A.; AlRabiah Haitham; Darwish Hany W.;

  • 作者单位

    King Saud Univ Coll Pharm Dept Pharmaceut Chem POB 2457 Riyadh 11451 Saudi Arabia;

    King Saud Univ Coll Pharm Dept Pharmaceut Chem POB 2457 Riyadh 11451 Saudi Arabia;

    King Saud Univ Coll Pharm Dept Pharmaceut Chem POB 2457 Riyadh 11451 Saudi Arabia;

    King Saud Univ Coll Pharm Dept Pharmaceut Chem POB 2457 Riyadh 11451 Saudi Arabia;

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  • 正文语种 eng
  • 中图分类 化学;
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