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 C_max of 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.

• Caco-2 cells
• CYP450
• drug–drug interaction
• oral absorption
• P-gp
• sorafenib

Declaration of interest

The authors have declared no conflict of interest. This study was financially supported by “The Youth Fund of Health Department of Fujian province (2012-2-47)”.