RT期刊文章SR电子T1 Infigratinib是可逆抑制剂和机理钝化剂的细胞色素P450 3 a4摩根富林明药物代谢和处理乔药物金属底座Dispos FD美国社会药理学和实验治疗SP 856 OP 868 10.1124 / dmd.121.000508 VO 雷竞技客服49是9 A1唐,劳埃德·魏答A1腾,Jian Wei A1 Verma, Ravi Kumar A1 Koh, Siew Kwan A1 Zhou, Lei A1 Go, Mei Lin A1 Fan, Hao A1 Chan,埃里克·春勇年2021 UL //www.1zgc.com/content/49/9/856.abstract AB Infigratinib(正)是一种很有前途的纤维母细胞生长因子受体的选择性抑制剂1 - 3最近给予孤儿药的名称和优先级审查状态由美国食品和药物管理局对先进的治疗胆管癌。最近对其对亲电物种进行生物活化的倾向进行了阐述。然而,除了引起异常的特殊毒性外,这些活性中间体还可能引起基于机制的细胞色素P450酶的失活。在本研究中,我们研究了INF与最丰富的肝脏CYP3A之间的相互作用。我们的研究结果显示,INF除了是一种有效的非竞争性可逆CYP3A4抑制剂外,还以时间、浓度和nadph依赖的方式灭活CYP3A4,灭活剂浓度为半最大灭活速率常数、最大灭活速率常数,分配比为4.17µM、0.068 min−1和41。分别为利伐沙班作为探针底物时。与睾酮(替代CYP3A底物)或酮康唑(直接CYP3A抑制剂)共孵育可降低失活率,而谷胱甘肽和过氧化氢酶并没有提供这种保护。 The lack of enzyme activity recovery after dialysis for 4 hours and oxidation with potassium ferricyanide, coupled with the absence of the characteristic Soret peak signature collectively substantiated that inactivation of CYP3A4 by INF was not mediated by the formation of quasi-irreversible metabolite-intermediate complexes but rather through irreversible covalent adduction to the prosthetic heme and/or apoprotein. Finally, glutathione trapping and high-resolution mass spectrometry experimental results unraveled two plausible bioactivation mechanisms of INF arising from the generation of a p-benzoquinonediimine and epoxide reactive intermediate.SIGNIFICANCE STATEMENT The potential of INF to cause MBI of CYP3A4 was unknown. This study reports the reversible noncompetitive inhibition and irreversible covalent MBI of CYP3A4 by INF and proposes two potential bioactivation pathways implicating p-benzoquinonediimine and epoxide reactive intermediates, following which a unique covalent docking methodology was harnessed to elucidate the structural and molecular determinants underscoring its inactivation. Findings from this study lay the groundwork for future investigation of clinically relevant drug-drug interactions between INF and concomitant substrates of CYP3A4.