Ty-Jour T1 - Infigratinib是一种可逆的抑制剂和基于机制的细胞色素P450 3A4 JF - 药物代谢和物理jo - 药物元代谢DO - 10.1124 / DMD.121.000508 SP 亚博体育app - DMD-AR-2021-000508 AU - TANG,Lloyd Wei Tat Au - Teng,Jian Wei Au - Verma,Ravi Kumar Au - Koh,Siew Kwan Au - Zhou,Lei Au - Go,Mei Lin Au - Fan,Hao Au - Chan,Eric Chun Yong Y1 - 2021/01 /01 UR - //www.3tejia.com/content/early/2021/08/02/dmd.121.000508.abstract n2 - Infigratinib(Inf)是最近的成纤维细胞生长因子受体1-3的有希望的选择性抑制剂been accorded both orphan drug designation and priority review status 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. ER -