RT期刊文章SR电子T1 Infigratinib是一种可逆抑制剂和基于机制的细胞色素P450 3A4的灭活剂JF药物代谢和处置Jo药物代谢Dimos FD美国药理学和实验治疗方法SP DMD-AR-2021-000508 DO 10.1124 / DMD。亚博体育app121.000508 A1 Tang,Lloyd Wei Tat A1 Teng,Jian Wei A1 Verma,Ravi Kumar A1 Koh,Siew Kwan A1 Zhou,Lei A1 Go,Mei Lin A1 Fan,Hao A1 Chan,Eric Chun Yong YR 2021 UL http:// DMD。Aspetjournals.org/content/early/2021/08/02/dmd.121.000508.Abstract Ab Infigratinib(INF)是最近被占孤儿药物指定和优先审查状况的成纤维细胞生长因子受体1-3的有前途的选择性抑制剂by the U.S Food and Drug Administration for the treatment of advanced cholangiocarcinoma. Its propensity to undergo bioactivation to electrophilic species was recently expounded upon. However, other than causing aberrant idiosyncratic toxicities, these reactive intermediates may elicit mechanism-based inactivation (MBI) of cytochrome P450 enzymes (CYP450). In this study, we investigated the interactions between INF and the most abundant hepatic cytochrome P450 3A4 (CYP3A4). Our findings revealed that apart from being a potent noncompetitive reversible inhibitor of CYP3A4, INF inactivated CYP3A4 in a time-, concentration- and NADPH-dependent manner with KI, kinact and partition ratio of 2.45 µM, 0.053 min-1 and 41 respectively when rivaroxaban was employed as the probe substrate. Co-incubation with testosterone (alternative CYP3A substrate) or ketoconazole (direct CYP3A inhibitor) attenuated the rate of inactivation whereas the inclusion of glutathione and catalase did not confer such protection. The lack of enzyme activity recovery following 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 unravelled two plausible bioactivation mechanisms of INF arising from the generation of a p-benzoquinone diimine and epoxide reactive intermediate. Significance Statement The potential of infigratinib (INF) to cause mechanism-based inactivation (MBI) of CYP3A4 was unknown. We report the reversible noncompetitive inhibition and irreversible covalent MBI of CYP3A4 by INF and proposed two potential bioactivation pathways implicating p-benzoquinone diimine and epoxide reactive intermediates. Findings from this study lay the groundwork for future investigation of clinically-relevant drug-drug interactions between INF and concomitant substrates of CYP3A4.