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

IF 6.9 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy Pub Date : 2024-10-04 DOI:10.1016/j.biopha.2024.117511

Jie Chen , Yingying Hu , Jinyu Hu , Zhize Ye , Qianmeng Lin , Jian-ping Cai , Guo-xin Hu , Ren-ai Xu

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Abstract

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.

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重组 CYP3A4 变体和相互作用对伊马替尼体外代谢的影响。

本研究旨在调查 26 种细胞色素 P450 3A4 (CYP3A4) 变体的催化活性以及药物相互作用对重组昆虫微粒体中伊马替尼代谢的影响。这项研究设计了适当的培养系统，并在恒温水中进行。利用超高效液相色谱-串联质谱法（UPLC-MS/MS）测定其代谢产物N-去甲基伊马替尼的数量，从而阐明CYP3A4基因多态性和药物相互作用对伊马替尼代谢的影响。结果发现，与 CYP3A4.1 相比，这些变异的内在清除率（CLint）值发生了显著变化，从 2.34% 上升到 120.57%。与 CYP3A4.1 相比，CYP3A4.14 的 CLint 值有所上升，其余 24 个变体在伊马替尼代谢方面的催化活性有所下降。此外，CYP3A4.1 和 CYP3A4.18 中的酮康唑、伊曲康唑和氟康唑也不同程度地降低了伊马替尼的代谢。此外，除了 6 个变体（CYP3A4.3、.4、.10、.15、.29 和.31）外，大多数 CYP3A4 变体在伊马替尼和卡博替尼的不同底物下的酶活性表现出相似的趋势。首次研究 26 个 CYP3A4 变体对伊马替尼代谢的影响将有助于伊马替尼的临床评估，并有助于在临床环境中进行个性化治疗。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biomedicine & Pharmacotherapy 医学-药学

CiteScore

11.90

自引率

2.70%

发文量

1621

审稿时长

48 days

期刊介绍： Biomedicine & Pharmacotherapy stands as a multidisciplinary journal, presenting a spectrum of original research reports, reviews, and communications in the realms of clinical and basic medicine, as well as pharmacology. The journal spans various fields, including Cancer, Nutriceutics, Neurodegenerative, Cardiac, and Infectious Diseases.