Inhibitory effect of propafenone on vortioxetine metabolism in vitro and in vivo

Abstract

Vortioxetine, as a new therapeutic drug of major depressive disorder (MDD), was approved for MDD in the USA. The significance of our study in this paper was to explore the inhibitory effect of propafenone on the metabolism of vortioxetine through the in vivo and in vitro experiments. In the vitro experiments, we added a series of concentrations of propafenone into an incubation system as the inhibitors and calculated the half-maximal inhibitory concentration (IC50) of propafenone on vortioxetine metabolism in human liver microsomes (HLMs) and rat liver microsomes (RLMs). Twelve male Sprague-Dawley (SD) rats were included in the vivo experiments. We randomly divided them into Group A (control group) and Group B (90 mg/kg propafenone). 30 min later, a single oral dose of 4.0 mg/kg vortioxetine was administrated to each rat. Then, we used ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) to determine the concentrations of vortioxetine and its metabolite Lu AA34443. From our results, it indicated that propafenone inhibited the metabolic rate of vortioxetine in the vitro studies with the IC50 of 0.48 μM and 16.5 μM for HLMs and RLMs, respectively. And, propafenone could competitively inhibit vortioxetine in both HLMs and RLMs for the inhibitory mechanisms. Moreover, a single oral dose of 90 mg/kg propafenone obviously enchanced the exposure of vortioxetine in rats, but not Lu AA34443. Combined with the vitro and vivo data, propafenone showed the inhibitory effect on vortioxetine metabolism. Thus, more attention to the safety of vortioxetine in clinic should be paid when taking it with propafenone in combination for the therapy.