Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore.
Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore
J Pharmacol Exp Ther. 2022 Aug;382(2):123-134. doi: 10.1124/jpet.122.001222. Epub 2022 May 31.
Infigratinib (INF) is a fibroblast growth factor receptor inhibitor that was recently United States Food and Drug Administration-approved for the treatment of advanced or metastatic cholangiocarcinoma. We previously established that INF inhibited and inactivated cytochrome P450 3A4 (CYP3A4). Here, in a follow up to our previous study, we identified for the first time that INF also elicited potent competitive inhibition and mechanism-based inactivation of CYP2J2 with kinetic parameters , , , and a partition ratio of 1.94 M, 0.10 M, 0.026 minute, and ∼3, respectively, when rivaroxaban was harnessed as the probe substrate. Inactivation was revealed to exhibit cofactor-dependency and was attenuated by an alternative substrate (astemizole) and direct inhibitor (nilotinib) of CYP2J2. Additionally, the nature of inactivation was unlikely to be pseudo-irreversible and instead arose from covalent modification due to the lack of substantial enzyme activity recovery after dialysis and chemical oxidation, as well as the lack of a resolvable Soret band in spectral scans. Glutathione trapping confirmed that the identity of the putative reactive intermediate implicated in the covalent inactivation of both CYP2J2 and CYP3A4 was identical and likely attributable to an electrophilic -benzoquinonediimine intermediate of INF. Finally, mechanistic static modeling revealed that by integrating the previously arcane inhibition and inactivation kinetic parameters of CYP2J2-mediated rivaroxaban hydroxylation by INF illuminated in this work, together with those previously documented for CYP3A4, a 49% increase in the systemic exposure of rivaroxaban was projected. Our modeling results predicted a potential risk of metabolic drug-drug interactions between the clinically relevant combination of rivaroxaban and INF in the setting of cancer. SIGNIFICANCE STATEMENT: This study reported that INF elicits potent reversible inhibition and mechanism-based inactivation of CYP2J2. Furthermore, static modelling predicted that its coadministration with the direct oral anticoagulant rivaroxaban may potentially culminate in a metabolic drug-drug interaction (DDI) leading to an increased risk of major bleeding. As rivaroxaban is steadily gaining prominence as the anticoagulant of choice in the treatment of cancer-associated venous thromboembolism, the DDI projections reported here are clinically relevant and warrant further investigation via physiologically based pharmacokinetic modelling and simulation.
英菲替尼（INF）是一种成纤维细胞生长因子受体抑制剂，最近被美国食品和药物管理局批准用于治疗晚期或转移性胆管癌。我们之前已经证实，INF 抑制和失活细胞色素 P450 3A4（CYP3A4）。在这里，作为我们之前研究的后续，我们首次发现 INF 还表现出对 CYP2J2 的强大竞争性抑制和基于机制的失活作用，动力学参数为 ， ， ，和分配比 1.94M，0.10M，0.026 分钟，和分别为 3，当利伐沙班被用作探针底物时。失活被证明具有辅酶依赖性，并且可以被 CYP2J2 的替代底物（阿斯特米唑）和直接抑制剂（尼洛替尼）减弱。此外，由于透析和化学氧化后酶活性没有明显恢复，以及光谱扫描中没有可分辨的 Soret 带，失活的性质不太可能是伪不可逆的，而是由于共价修饰引起的。谷胱甘肽捕获证实，涉及 CYP2J2 和 CYP3A4 共价失活的假定反应中间体的身份相同，并且可能归因于 INF 的亲电 -苯醌二亚胺中间体。最后，机制静态模型表明，通过整合之前在这项工作中阐明的 CYP2J2 介导的利伐沙班羟化的 INF 抑制和失活动力学参数，以及之前为 CYP3A4 记录的参数，预计利伐沙班的系统暴露量将增加 49%。我们的建模结果预测，在癌症环境下，INF 与临床上相关的利伐沙班联合使用可能存在潜在的代谢药物相互作用风险。意义声明：本研究报告称，INF 可引起 CYP2J2 的强烈可逆抑制和基于机制的失活。此外，静态模型预测，其与直接口服抗凝剂利伐沙班联合使用可能会导致潜在的代谢药物相互作用（DDI），从而增加大出血的风险。由于利伐沙班作为癌症相关静脉血栓栓塞症治疗中首选的抗凝剂日益受到关注，因此，这里报告的 DDI 预测具有临床相关性，需要通过生理相关的药代动力学模型和模拟进一步研究。
