Dabrafenib是一种BRAF抑制剂，已被证明对治疗具有BRAF V600E突变的黑色素瘤和非小细胞肺癌患者有效。本研究旨在探讨51种中药对达拉非尼代谢的影响，并进一步探讨欧前胡素的抑制作用。采用基于超高效液相色谱串联质谱 (UPLC-MS/MS) 的灵敏、快速、准确的测定方法对达拉非尼及其代谢物羟基达拉非尼进行定量。体外实验结果显示，20种药物对达拉非尼的代谢抑制超过80%。在进一步研究欧前胡素对达拉非尼的作用时，在大鼠肝微粒体（RLM）和人肝微粒体（HLM）中，欧前胡素对达拉非尼的半数最大抑制浓度（IC50）值分别为0.22μM和3.68μM，而抑制机制分别为非竞争性抑制和混合型抑制。体内实验结果表明，在欧前胡素存在下，达拉非尼的AUC(0-t)、AUC(0-∞)、Cmax和Tmax增加了2.38-、2.26-、1.05-和6.10-倍，而 CLz/F 降低了 67.9%。此外，羟基达拉非尼的 Tmax 增加了 1.4 倍。研究结果表明，欧前胡素在体外和体内对达拉非尼具有一致的抑制作用。当达拉非尼和欧前胡素同时使用不可避免时，临床医生应密切监测潜在的不良事件，并及时调整给药剂量。版权所有 © 2024。由 Elsevier B.V. 出版。

Dabrafenib is a BRAF inhibitor that has been demonstrated to be efficacious in the treatment of melanoma and non-small-cell lung cancer patients with BRAF V600E mutations. The objective of this study was to investigate the effects of 51 traditional Chinese medicines on the metabolism of dabrafenib and to further investigate the inhibitory effect of imperatorin. The quantification of dabrafenib and its metabolite hydroxy-dabrafenib was carried out using a sensitive, rapid, and accurate assay method based on ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The results of in vitro experiments showed that 20 drugs inhibited the metabolism of dabrafenib by more than 80%. In a further study of imperatorin on dabrafenib, the half-maximal inhibitory concentration (IC50) values of imperatorin on dabrafenib were 0.22 μM and 3.68 μM in rat liver microsomes (RLM) and human liver microsomes (HLM), respectively, while the inhibition mechanisms were non-competitive and mixed type inhibition, respectively. The results of in vivo experiments demonstrated that in the presence of imperatorin, the AUC(0-t), AUC(0-∞), Cmax, and Tmax of dabrafenib were increased by 2.38-, 2.26-, 1.05-, and 6.10-fold, respectively, while CLz/F was decreased by 67.9%. In addition, Tmax of hydroxy-dabrafenib was increased by 1.4-fold. The results of the research showed that imperatorin had a consistent inhibitory effect on dabrafenib in vitro and in vivo. When the concurrent use of dabrafenib and imperatorin is unavoidable, clinicians should closely monitor for potential adverse events and make timely adjustments to the administered dosage.Copyright © 2024. Published by Elsevier B.V.