Abstract：
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.
摘要：
Dabrafenib是一种BRAF抑制剂，已被证明可有效治疗具有BRAFV600E突变的黑色素瘤和非小细胞肺癌患者。本研究的目的是研究51种中药对达拉非尼代谢的影响，并进一步研究欧前胡素的抑制作用。dabrafenib及其代谢产物羟基-dabrafenib的定量是使用灵敏的，快速,基于超高效液相色谱串联质谱(UPLC-MS/MS)的检测方法。体外实验结果表明，20种药物对dabrafenib的代谢抑制超过80％。在Dabrafenib上欧前胡素的进一步研究中，在大鼠肝微粒体（RLM）和人肝微粒体（HLM）中，欧前胡素对dabrafenib的半数最大抑制浓度（IC50）分别为0.22μM和3.68μM，分别,而抑制机制是非竞争性和混合型抑制，分别。体内实验的结果表明，在欧前胡素的存在下，AUC（0-t），AUC(0-∞)，Cmax,达拉非尼的Tmax增加了2.38-，2.26-，1.05-，和6.10倍，分别,而CLz/F下降了67.9%。此外,羟基-dabrafenib的Tmax增加了1.4倍。研究结果表明欧前胡素对达拉非尼的体内外抑制作用一致。当无法避免同时使用达拉非尼和欧前胡素时，临床医师应密切监测潜在的不良事件,并及时调整给药剂量.
