Simultaneous Determination of Sorafenib and Dapagliflozin in Rat Plasma by UPLC MS-MS Method with Application in Pharmacokinetic Interactions Study

Hepatocellular carcinoma (HCC) and type 2 diabetes mellitus (T2DM) are common in clinical conditions, and T2DM is a significant risk factor for HCC. Sorafenib (SOR), the multiple kinases inhibitor, is the first-line therapy for advanced HCC. Dapagliflozin (DAPA), a sodium-glucose cotransporter-2 inhibitor (SGLT2i), is widely used in patients with T2DM. Co-administration of SOR with DAPA is possible in clinical settings. The purpose of this study was to develop an ultra-performance lipid chromograph mass spectrum (UPLC-MS/MS) method to determine SOR and DAPA simultaneous and to investigate the pharmacokinetic interactions between SOR and DAPA. Liquid-liquid extraction was performed for sample preparation and the Chromatographic separation was conducted on Waters XSelect HSS T3 column with a gradient elution of 0.1% formic acid and 5mM-ammonium acetate in ultrapure water (Phase A) and acetonitrile (Phase B). Mass quantification was carried out in positive-ion multiple reaction monitoring mode. The animals were randomly divided into seven groups. Single dose groups 1,2 were treated with SOR and DAPA, respectively and group 3 received SOR and DAPA. Multiple-doses groups 4,5 were treated with 7-days solvents and DAPA, respectively, followed by SOR, groups 6,7 were administered with 7-days solvents and SOR, respectively, followed by DAPA. All concentrations were analyzed by the validated method. The main pharmacokinetic parameters were calculated statistically. Satisfactory linearities, precision, accuracy, recovery, matrix effect and stability were obtained. The method was successfully applied to pharmacokinetic interactions study. There were no significant pharmacokinetic changes in SOR and DAPA in single-dose groups. In multiple-doses groups, the C max and AUC for SOR decreased and the CL z and V z increased. The AUC, MRT and t 1/2z for DAPA increased and the CL z reduced. Drug-drug interactions (DDIs) existed between long-term SOR and DAPA, and active surveillance for the treatment outcomes and adverse reactions are required. The further studies of exact mechanism and pharmacodynamics are needed to encourage the safe use of this combination.