Inhibitory mechanism of vortioxetine on CYP450 enzymes in human and rat liver microsomes

Vortioxetine is a novel anti-major depression disorder drug with high safety profile compared other similar drugs. However, little research has been done on drug-drug interactions (DDI) about vortioxetine. In this paper, the inhibitory effect of vortioxetine cytochrome P450 (CYP450) and type mechanism were investigated in human rat liver microsomes. We set up an vitro incubation system 200 μL to measure metabolism probe substrates at present 37°C. The concentrations metabolites all measured by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method. It was found no time-dependent inhibition (TDI) through determination half-maximal concentration (IC 50 ) shift values. enzymes involved experiment rats as follows: CYP3A4/CYP3A (midazolam); CYP2B6/CYP2B (bupropion); CYP2D6/CYP2D (dextromethorphan); CYP2C8/CYP2C-1 (amodiaquine); CYP2C9/CYP2C-2 (losartan); CYP2C19/CYP2C-3 (mephenytoin). that competitively inhibited CYP2C19 CYP2D6 microsomes (HLMs) constant (K i values 2.17 μM 9.37 μM, respectively. noncompetitive for CYP3A4 CYP2C8, its K 7.26 6.96 For CYP2B6 CYP2C9, exhibited mixed 8.55 4.17 RLMs, uncompetitive CYP3A CYP2D = 4.41 100.9 μM). competitive inhibition, including CYP2B CYP2C-2 2.87 0.12 types CYP2C-1 CYP2C-3 39.91 4.23 μM) study above will provide guidance safe clinical use so occurrence DDI can be avoided.