Inhibitory effect of Schisandrin on the pharmacokinetics of poziotinib in vivo and in vitro by UPLC‐MS/MS

Abstract

AbstractBackgroundAs a pan‐HER tyrosine kinase inhibitor with a promising application prospect, poziotinib is likely to be coadministered with Schisandrins in clinical treatment due to its anticancer activities.MethodsEighteen Sprague–Dawley rats were randomly divided into three groups: Schisandrin A group and Schisandrin B group (20 mg/kg daily for 1 week), and control group (vehicle). On day 8, poziotinib (2 mg/kg) was administered by oral gavage 30 min later. An in vitro study was developed to identify the possible mechanisms of Schisandrins on poziotinib metabolism. All analytes were detected by UPLC/MS–MS, and molecular docking was performed by AutoDock Tools.ResultsWhen rats were preadministered with Schisandrin A, AUC(0−∞) and Cmax of poziotinib were obviously increased by 0.79‐ and 1.17‐fold, whereas the Vz/F and CLz/F values were dramatically decreased. The results in Schisandrin B group presented similarly. Both Schisandrin A and Schisandrin B were mixed inhibitors of poziotinib in RLMs, and Schisandrin B showed stronger inhibitory activity with IC50 values of 2.55 μM for M1 and 6.97 μM for M2. Molecular docking analysis demonstrated that Schisandrin A and Schisandrin B exhibited a strong binding ability towards CYP2D6 as compared to CYP3A4.ConclusionAll results provided the direct evidence of the pharmacokinetic drug–drug interactions (DDIs) between Schisandrin and poziotinib. Thus, particular attention should be paid when poziotinib is taken together with Schisandrins in clinical practice.