Development of a validated LC-MS/MS method for quantification of phosphoinositide 3 kinase inhibitor GSK2636771: Application to a pharmacokinetic study in rat plasma

摘要

A simple and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) coupled with one-step protein precipitation extraction method was developed and validated for determination of GSK2636771, a phosphoinositide 3 kinase (PI3K) inhibitor in rat plasma, After protein precipitation with acetonitrile, the chromatographic separation was carried out on a CORTECS UPLC C-18 column, with acetonitrile and 0.1 % formic acid in water as mobile phase at a flow rate of 0.30 mL.min(-1). The detection was performed on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring (MRM) mode via electrospray ionization (ESI) source, with target quantitative ion pairs of m/z 434.2 -> 416.2 for GSK2636771, and 411.2 -> 367.2 for BKM120 (internal standard). The calibration curve was linear over the range of 2.0-8000 ng.mL(-1), and the LLOQ was evaluated to be 2.0 ng.mL(-1). The accuracy (relative error, RE %) ranged from -3.4 % to 4.7 %, and the intra- and inter-day precision were within 15 %, and with the mean extraction recovery 82.1-89.3 %. The validated method described a quantification method of GSK2636771 in detail for the first time and applied to a pharmacokinetic study after oral administration of GSK2636771 at low, medium and high doses in rats. The mean plasma concentration versus time profiles of GSK2636771 showed a dose-dependent relationship at different doses. (C) 2019 Elsevier B.V. All rights reserved.