Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou, China.
Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China.
J Sep Sci. 2024 Mar;47(5):e2300923. doi: 10.1002/jssc.202300923.
Regorafenib is a small-molecule tyrosine kinase inhibitor with severe hepatotoxicity. It undergoes metabolism mainly by CYP3A4 to generate active metabolites regorafenib-N-oxide (M2) and N-desmethyl-regorafenib-N-oxide (M5). Wuzhi capsule (WZC) is an herbal preparation derived from Schisandra sphenanthera and is potentially used to prevent regorafenib-induced hepatotoxicity. This study aims to explore the effect of WZC on the pharmacokinetics of regorafenib in rats. An efficient and sensitive liquid chromatography-tandem mass spectrometry method was developed to quantitatively determine regorafenib and its main metabolites in rat plasma. The proposed method was applied to the pharmacokinetic study of regorafenib in rats, with or without WZC. Coadministration of regorafenib with WZC resulted in a prolonged mean residence time (MRT) of the parent drug but had no statistically significant difference in other pharmacokinetic parameters. While for the main metabolites of regorafenib, WZC decreased the area under the curve and maximum concentration (C ), delayed the time to reach C , and prolonged the MRT of M2 and M5. These results indicate that WZC delayed and inhibited the metabolism of regorafenib to M2 and M5 by suppressing CYP3A4. Our study provides implications for the rational use of the WZC-regorafenib combination in clinical practice.
瑞戈非尼是一种小分子酪氨酸激酶抑制剂，具有严重的肝毒性。它主要通过 CYP3A4 代谢生成活性代谢物瑞戈非尼-N-氧化物（M2）和 N-去甲基-瑞戈非尼-N-氧化物（M5）。五酯胶囊（WZC）是一种从五味子中提取的草药制剂，可能用于预防瑞戈非尼引起的肝毒性。本研究旨在探讨 WZC 对大鼠体内瑞戈非尼药代动力学的影响。建立了一种高效灵敏的液相色谱-串联质谱法，定量测定大鼠血浆中的瑞戈非尼及其主要代谢物。该方法应用于瑞戈非尼在大鼠体内的药代动力学研究，包括 WZC 给药组和对照组。瑞戈非尼与 WZC 合用使母体药物的平均驻留时间（MRT）延长，但其他药代动力学参数无统计学差异。而对于瑞戈非尼的主要代谢物，WZC 降低了 AUC 和 C ，延迟了 C 的达峰时间，并延长了 M2 和 M5 的 MRT。这些结果表明，WZC 通过抑制 CYP3A4 来延缓和抑制瑞戈非尼向 M2 和 M5 的代谢。本研究为临床实践中 WZC-瑞戈非尼联合用药的合理应用提供了依据。
