Effect of recombinant CYP3A4 variants and interaction on imatinib metabolism in vitro

作者：Jie Chen, Yingying Hu, Jinyu Hu, Zhize Ye, Qianmeng Lin, Jianping Cai, Guo‐Xin Hu, Ren-ai Xu · 发表于：Biomedicine & Pharmacotherapy · 年份：2024 · DOI：10.1016/j.biopha.2024.117511 · 被引用次数：6 · 研究领域：Chronic Myeloid Leukemia Treatments、Platelet Disorders and Treatments、Gastrointestinal Tumor Research and Treatment

The aim of this study was to investigate the catalytic activity of 26 Cytochrome P450 3A4 (CYP3A4) variants and drug interactions on imatinib metabolism in recombinant insect microsomes. This study was designed with an appropriate incubation system and carried out in the constant temperature water. By using ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) to measure the quantities of its metabolite N -desmethyl imatinib, to elucidate the impacts of the CYP3A4 genetic polymorphism and drug interactions on the metabolism of imatinib. Consequently, as compared to CYP3A4.1, the intrinsic clearance (CL int ) values of the variations were dramatically changed, rising from 2.34 % to 120.57 %. CYP3A4.14 showed an increase in CL int in comparison to CYP3A4.1, and the remaining 24 variants demonstrated decreases in catalytic activity for the metabolism of imatinib. In addition, the metabolism of imatinib was decreased to varied degrees by ketoconazole, itraconazole, and fluconazole in CYP3A4.1 and CYP3A4.18. Moreover, most of CYP3A4 variants showed similar trend of enzyme activity under different substrates of imatinib and cabozantinib, except 6 variants (CYP3A4.3,.4,.10,.15,.29 and.31). The first study of the effects of 26 CYP3A4 variants on imatinib metabolism will contribute to the clinical evaluation of imatinib and help personalize therapy in clinical settings.