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 (Cmax), delayed the time to reach Cmax, 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.

中文翻译：

---

液相色谱-串联质谱法探讨五脂胶囊对瑞戈非尼及其主要代谢物在大鼠血浆中药动学的影响

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。主要通过CYP3A4代谢产生活性代谢物瑞戈非尼-氮‐氧化物 (M2) 和氮‐去甲基‐瑞格非尼‐氮‐氧化物（M5）。五脂胶囊（WZC）是一种草药制剂，源自华中五味子并有可能用于预防瑞格非尼引起的肝毒性。本研究旨在探讨WZC对瑞戈非尼在大鼠体内药代动力学的影响。开发了一种高效、灵敏的液相色谱-串联质谱方法来定量测定大鼠血浆中的瑞戈非尼及其主要代谢物。所提出的方法适用于瑞戈非尼在有或没有 WZC 的大鼠体内的药代动力学研究。瑞戈非尼与 WZC 联合给药导致母体药物的平均停留时间 (MRT) 延长，但其他药代动力学参数无统计学显着差异。而对于瑞戈非尼的主要代谢物，WZC 降低了曲线下面积和最大浓度（C最大限度），延迟了到达C的时间最大限度，并延长了M2和M5的MRT。这些结果表明，WZC 通过抑制 CYP3A4 延迟和抑制瑞戈非尼向 M2 和 M5 的代谢。我们的研究为临床实践中合理使用 WZC-瑞戈非尼组合提供了启示。