Inhibitory effect of imperatorin on dabrafenib metabolism in vitro and in vivo

作者全名："Xia, Hailun; Wu, Hualu; Chen, Jie; Xu, Xinhao; Tan, Wei; Xu, Ren-ai"

作者地址："[Xia, Hailun; Chen, Jie; Xu, Xinhao; Xu, Ren-ai] Wenzhou Med Univ, Dept Pharm, Affiliated Hosp 1, Wenzhou, Zhejiang, Peoples R China; [Wu, Hualu; Xu, Ren-ai] Wenzhou Med Univ, Affiliated Hosp 1, Key Lab Diag & Treatment Severe Hepatopancreat Dis, Wenzhou, Zhejiang, Peoples R China; [Tan, Wei] Chongqing Med Univ, Affiliated Hosp 3, Gener Hosp, Chongqing, Peoples R China"

通信作者："Xu, RA (通讯作者)，Wenzhou Med Univ, Dept Pharm, Affiliated Hosp 1, Wenzhou, Zhejiang, Peoples R China.; Tan, W (通讯作者)，Chongqing Med Univ, Affiliated Hosp 3, Gener Hosp, Chongqing, Peoples R China."

来源：CHEMICO-BIOLOGICAL INTERACTIONS

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:001270677200001

JCR分区：Q1

影响因子：5.1

年份：2024

卷号：399

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Dabrafenib; Imperatorin; Drug -drug interaction; Pharmacokinetic

摘要："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 mu M and 3.68 mu M 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-infinity), 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 hydroxydabrafenib 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."

基金机构："National Natural Science Foundation of China [82104297, WYYY-IACUC-AEC-2024-020]"

基金资助正文：<BOLD> This work was supported by the National Natural Science Foundation of China (82104297) . </BOLD> The animal study has been supervised and approved by Institutional Animal Care and Use Committee of The First Affiliated Hospital of Wenzhou Medical University. (WYYY-IACUC-AEC-2024-020) .