Department of Pharmacology, School of Pharmacy, Wenzhou Medical University, Wenzhou, China.
The Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing, China.
Basic Clin Pharmacol Toxicol. 2019 Oct;125(4):337-344. doi: 10.1111/bcpt.13246. Epub 2019 Jun 18.
Regorafenib is a tyrosine kinase inhibitor that is mainly metabolized by CYP3A4. The genetic polymorphism of CYP3A4 would contribute to differences in metabolism of regorafenib. Previously, we had discovered several novel CYP3A4 variants. However, the catalytic characteristics of these 27 CYP3A4 variants on oxidizing regorafenib have not being determined. The purpose of this study was to investigate the catalytic characteristics of 27 CYP3A4 protein variants on the oxidative metabolism of regorafenib in vitro.
Wild-type CYP3A4.1 or other variants was incubated with 0.5-20 μmol/L regorafenib for 30 minutes. After sample processing, regorafenib-N-oxide, a primary metabolite, was detected by ultra-performance liquid chromatography-tandem mass spectrometry system.
CYP3A4.20 had no detectable enzyme activity compared with wild-type CYP3A4.1; five variants (CYP3A4.5, .16, .19, .24, .29) exhibited similar clearance value with CYP3A4.1; four variants (CYP3A4.14, .15, .28, .31) displayed increased enzymatic activities, while remaining variants showed markedly decreased intrinsic clearance values.
This study is the first to investigate the function of 27 CYP3A4 protein variants on the metabolism of regorafenib in vitro, and it may provide some valuable information for further research in clinic.
瑞戈非尼是一种主要由 CYP3A4 代谢的酪氨酸激酶抑制剂。CYP3A4 的遗传多态性可能导致瑞戈非尼代谢的差异。先前，我们已经发现了几种新的 CYP3A4 变体。然而，这些 27 种 CYP3A4 变体氧化瑞戈非尼的催化特性尚未确定。本研究旨在探讨 27 种 CYP3A4 蛋白变体在体外氧化代谢瑞戈非尼的催化特性。
野生型 CYP3A4.1 或其他变体与 0.5-20 μmol/L 的瑞戈非尼孵育 30 分钟。样品处理后，通过超高效液相色谱-串联质谱系统检测主要代谢产物瑞戈非尼-N-氧化物。
与野生型 CYP3A4.1 相比，CYP3A4.20 没有检测到酶活性；五种变体（CYP3A4.5、.16、.19、.24、.29）的清除率与 CYP3A4.1 相似；四种变体（CYP3A4.14、.15、.28、.31）显示出增强的酶活性，而其余变体显示出明显降低的内在清除率。
本研究首次研究了 27 种 CYP3A4 蛋白变体在体外代谢瑞戈非尼的功能，这可能为进一步的临床研究提供一些有价值的信息。
