Simultaneous quantification of vortioxetine, carvedilol and its active metabolite 4-hydroxyphenyl carvedilol in rat plasma by UPLC-MS/MS: Application to their pharmacokinetic interaction study

To establish a rapid and sensitive ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for the determination of vortioxetine, carvedilol and its metabolite 4-hydroxyphenyl carvedilol in rat plasma. The analytes and the internal standard (diazepam) were separated on an Acquity UPLC BEH C18 chromatography column (2.1 mm x 50 mm, 1.7 mu m) using gradient elution with a mobile phase of acetonitrile and 0.1% formic acid in water at a flow rate of 0.4 mi./min. The detection was performed on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring (MRM) mode to monitor the precursor-to-product ion transitions of m/z 299.2 -> 150.1 for vortioxetine, m/z 407.2 -> 100.3 for carvedilol, m/z 423.2 -> 100.1 for 4-hydroxyphenyl carvedilol and m/z 285.2 -> 193.1 for diazepam (IS) using a positive electrospray ionization interface. The method was validated over a concentration range of 0.5-100 ng/mL for vortioxetine, 0.5-1000 ng/mL for carvedilol and 0.1-50 ng/mL for 4-hydroxyphenyl carvedilol. Total time for each chromatograph was 3.0 min. The intraand inter-day precision and accuracy of the quality control samples at low, medium, and high concentration levels exhibited relative standard deviations (RSD) < 11.6% and the accuracy values ranged from -12.2% to 11.3%. The analytical method was successfully applied to a pharmacokinetic interaction study of vortioxetine and carvedilol after oral administration vortioxetine and carvedilol in rats. Results suggested that the co-administration of vortioxetine and carvedilol results in a significant drug interaction in rats. (C) 2016 Elsevier B.V. All rights reserved.