Determination of a novel phosphodiesterase-4 inhibitor chlorbipram in mouse plasma and brain by UFLC-MS/MS: Application in pharmacokinetic studies after intravenous administration

摘要

In this study, we evaluated a simple and sensitive method for determination of a novel phosphodiesterase-4 (PDE4) inhibitor, chlorbipram, in mouse plasma and brain using ultra-fast liquid chromatography-tandem mass spectrometry (UFLC-MS/MS). Separation was achieved using an Acquity UPLC BEH C18 column (50 mm x 2.1 mm, particle size 1.7 mu m) with a gradient mobile phase consisting of water and methanol at a flow rate of 0.25 ml/min. Detection was performed in the multiple reaction monitoring (MRM) mode using electrospray ionization (ESI) in the positive ion mode. The liquid-liquid extraction method with ethyl acetate was used for both pretreatment of plasma and brain homogenates. The calibration curves of chlorbipram showed good linearity over the concentration range of 0.5-200 ng/ml (R-2 > 0.994) for mouse plasma and over the range of 0.25-100 ng/ml (R-2 > 0.994) for mouse brain homogenate. The extraction recovery was in the range of 78.3-84.8% for chlorbipram and the internal standard (IS) ZXI14 in two different biological matrices. The intra- and inter-day precision values were less than 13.0% and the accuracy ranged from 97.8% to 106.0% for quality control samples. No noteworthy matrix effects and instability were observed for chlorbipram. This validated method was successfully applied to a pharmacokinetic study of chlorbipram in mice after intravenous administration. The results show that this novel drug crosses the blood-brain barrier and provides the basis for further studies on chlorbipram. (C) 2015 Elsevier B.V. All rights reserved.