title: The drug-drug interaction of sorafenib mediated by P-glycoprotein and CYP3A4.
abstract: 1. The aim of this study was to investigate the potential drug-drug interaction of sorafenib mediated by P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4). 2. In this research, a sensitive and reliable LC-MS/MS method was developed and applied for the determination of sorafenib in rat plasma. The pharmacokinetic profiles of orally administered sorafenib from rats with and without verapamil pretreatment were investigated. 3. The results indicated that when the rats were pretreated with verapamil, the Cmaxof sorafenib increased from 55.73 ng/ml to 87.72 ng/ml (57.40%), and the AUC(0-t)increased by approximately 58.2% when sorafenib was co-administered with verapamil. Additionally, the effects of verapamil on the absorption of sorafenib were investigated using the Caco-2 cell transwell model, and the effects of verapamil on the metabolic stability of sorafenib were also studied using rat liver microsomes incubation systems. A markedly higher transport of sorafenib across the Caco-2 cells was observed in the basolateral-to-apical direction and was abrogated in the presence of the P-gp inhibitor, verapamil. The results indicated that P-gp was involved in the transport of sorafenib, and verapamil could increase its absorption in the Caco-2 cell model, and the metabolic stability of sorafenib was prolonged by the pretreatment with verapamil. 4. In conclusion, the drug-drug interaction of sorafenib might happen when sorafenib was co-administered with P-gp or CYP3A4 inhibitors.
authors.affiliation: a The First Clinical Medical College of Fujian Medical University , Fuzhou , China.
authors.forename: Xianming
authors.initials: X
authors.lastname: Wang
authors.affiliation: a The First Clinical Medical College of Fujian Medical University , Fuzhou , China.|c The First Affiliated Hospital of Fujian Medical University , Fuzhou , China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhang
authors.affiliation: b Department of Hepatobiliary Surgery , The Mengchao Hepatobiliary Surgery Hospital, Fujian Medical University , Fuzhou , China , and.
authors.forename: Xinhui
authors.initials: X
authors.lastname: Huang
authors.affiliation: b Department of Hepatobiliary Surgery , The Mengchao Hepatobiliary Surgery Hospital, Fujian Medical University , Fuzhou , China , and.
authors.forename: Yuntong
authors.initials: Y
authors.lastname: Li
authors.affiliation: a The First Clinical Medical College of Fujian Medical University , Fuzhou , China.|b Department of Hepatobiliary Surgery , The Mengchao Hepatobiliary Surgery Hospital, Fujian Medical University , Fuzhou , China , and.
authors.forename: Mengchao
authors.initials: M
authors.lastname: Wu
authors.affiliation: a The First Clinical Medical College of Fujian Medical University , Fuzhou , China.|b Department of Hepatobiliary Surgery , The Mengchao Hepatobiliary Surgery Hospital, Fujian Medical University , Fuzhou , China , and.
authors.forename: Jingfeng
authors.initials: J
authors.lastname: Liu
keywords: CYP450; Caco-2 cells; P-gp; drug–drug interaction; oral absorption; sorafenib