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Mechanism-Based Inactivation of Cytochrome P450 3A4 and 3A5 by the Fibroblast Growth Factor Receptor Inhibitor Erdafitinib
Chemical Research in Toxicology ( IF 4.1 ) Pub Date : 2021-06-30 , DOI: 10.1021/acs.chemrestox.1c00178
Lloyd Wei Tat Tang 1 , Jian Wei Teng 1 , Siew Kwan Koh 2 , Lei Zhou 2, 3, 4 , Mei Lin Go 1 , Eric Chun Yong Chan 1
Affiliation  

Erdafitinib (ERD) is a first-in-class pan inhibitor of fibroblast growth factor receptor 1–4 that has garnered global regulatory approval for the treatment of advanced or metastatic urothelial carcinoma. Although it has been previously reported that ERD elicits time-dependent inhibition (TDI) of cytochrome P450 (P450) 3A4 (CYP3A4), the exact biochemical nature underpinning this observation remains obfuscated. Moreover, it is also uninterrogated if CYP3A5—its highly homologous counterpart—could be susceptible to such interactions. Mechanism-based inactivation (MBI) of P450 is a unique subset of TDI that hinges on prior bioactivation of the drug to a reactive intermediate and possesses profound clinical and toxicological implications due to its irreversible nature. Here, we investigated and confirmed that ERD inactivated both CYP3A isoforms in a time-, concentration-, and NADPH-dependent manner with KI, kinact, and partition ratio of 4.01 and 10.04 μM, 0.120 and 0.045 min–1, and 32 and 55 for both CYP3A4 and CYP3A5, respectively, when rivaroxaban was employed as the probe substrate. Co-incubation with an alternative substrate or direct inhibitor of CYP3A attenuated the rate of inactivation, whereas the addition of glutathione or catalase did not induce such protection. The lack of enzyme activity recovery following dialysis for 4 h and oxidation with potassium ferricyanide combined with the lack of a Soret peak in spectral scans collectively substantiated that ERD is an irreversible covalent MBI of CYP3A. Finally, glutathione trapping and high-resolution mass spectrometry experiments illuminated a plausible bioactivation mechanism of ERD by CYP3A arising from metabolic epoxidation of its quinoxaline ring.

中文翻译:

成纤维细胞生长因子受体抑制剂 Erdafitinib 基于机制的细胞色素 P450 3A4 和 3A5 灭活

Erdafitinib (ERD) 是一种一流的成纤维细胞生长因子受体 1-4 泛抑制剂,已获得全球监管机构批准用于治疗晚期或转移性尿路上皮癌。尽管之前有报道称 ERD 会引起细胞色素 P450 (P450) 3A4 (CYP3A4) 的时间依赖性抑制 (TDI),但支持这一观察结果的确切生化性质仍不清楚。此外,CYP3A5——其高度同源的对应物——是否容易受到这种相互作用的影响也没有受到质疑。P450 的基于机制的灭活 (MBI) 是 TDI 的一个独特子集,它取决于药物预先生物活化为反应性中间体,并且由于其不可逆的性质而具有深刻的临床和毒理学意义。这里,K Ik inact和分配比分别为 4.01 和 10.04 μM,0.120 和 0.045 min –1当利伐沙班用作探针底物时,CYP3A4 和 CYP3A5 分别为 32 和 55。与 CYP3A 的替代底物或直接抑制剂共同孵育会降低失活率,而添加谷胱甘肽或过氧化氢酶不会诱导这种保护。透析 4 小时后酶活性恢复缺乏,铁氰化钾氧化,加上光谱扫描中缺乏 Soret 峰,共同证实 ERD 是 CYP3A 的不可逆共价 MBI。最后,谷胱甘肽捕获和高分辨率质谱实验阐明了 CYP3A 对 ERD 的合理生物激活机制,其由喹喔啉环的代谢环氧化引起。
更新日期:2021-07-19
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