title: Determination of a novel phosphodiesterase-4 inhibitor chlorbipram in mouse plasma and brain by UFLC-MS/MS: Application in pharmacokinetic studies after intravenous administration.
abstract: 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 (50mm×2.1mm, particle size 1.7μm) with a gradient mobile phase consisting of water and methanol at a flow rate of 0.25ml/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 0.5-200ng/ml (R(2)>0.994) for mouse plasma and over the range of 0.25-100ng/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.
authors.affiliation: Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutial Sciences, Southern Medical University, Guangzhou 510515, China.
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Li
authors.affiliation: Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutial Sciences, Southern Medical University, Guangzhou 510515, China.
authors.forename: Yufang
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutial Sciences, Southern Medical University, Guangzhou 510515, China.
authors.forename: Bingqing
authors.initials: B
authors.lastname: Zeng
authors.affiliation: Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutial Sciences, Southern Medical University, Guangzhou 510515, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Niu
authors.affiliation: Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutial Sciences, Southern Medical University, Guangzhou 510515, China.
authors.forename: Haibiao
authors.initials: H
authors.lastname: Guo
authors.affiliation: School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou 510515, China.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Li
authors.affiliation: Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutial Sciences, Southern Medical University, Guangzhou 510515, China.
authors.forename: Hongfang
authors.initials: H
authors.lastname: Feng
authors.affiliation: Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutial Sciences, Southern Medical University, Guangzhou 510515, China.
authors.forename: Jiangping
authors.initials: J
authors.lastname: Xu
authors.affiliation: School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou 510515, China. Electronic address: xujp@smu.edu.cn.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Yang
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D002138:Calibration; D002853:Chromatography, Liquid / Q000379:methods*; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D058988:Phosphodiesterase 4 Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D011724:Pyridazines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: D058988:Phosphodiesterase 4 Inhibitors; D011724:Pyridazines; C000589512:chlorbipram
keywords: Chlorbipram; Pharmacokinetics; Phosphodiesterase-4 inhibitor; UFLC–MS/MS