Determination of Meserine, a new candidate for Alzheimer's disease in mice brain by liquid chromatography-tandem mass spectrometry and its application to a pharmacokinetic and tissue distribution study.
A rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for determination of Meserine ((-)-meptazinol phenylcarbamate), a novel potent inhibitor of acetylcholinesterase (AChE), was developed, validated, and applied to a pharmacokinetic study in mice brain. The lower limit of quantification (LLOQ) was 1 ng mL(-1) and the linear range was 1-1,000 ng mL(-1). The analyte was eluted on a Zorbax SB-Aq column (2.1 × 100 mm, 3.5 μm) with the mobile phase composed of methanol and water (70:30, v/v, aqueous phase contained 10 mM ammonium formate and 0.3% formic acid) using isocratic elution, and monitored by positive electrospray ionization in multiple reaction monitoring (MRM) mode. The flow rate was 0.25 mL min(-1). The injection volume was 5 μL and total run time was 4 min. The relative standard deviation (RSD) of intraday and interday variation was 2.49-7.81 and 3.01-7.67%, respectively. All analytes were stable after 4 h at room temperature and 6 h in autosampler. The extraction recoveries of Meserine in brain homogenate were over 90%. The main brain pharmacokinetic parameters obtained after intranasal administration were T max = 0.05 h, C max = 462.0 ± 39.7 ng g(-1), T 1/2 = 0.4 h, and AUC(0-∞) = 283.1 ± 9.1 ng h g(-1). Moreover, Meserine was distributed rapidly and widely into brain, heart, liver, spleen, lung, and kidney tissue. The method is validated and could be applied to the pharmacokinetic and tissue distribution study of Meserine in mice.
Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, China.
Zhaoxi
Z
Zheng
Yabin
Y
Tang
Haoyu
H
Lv
Jianrong
J
Xu
Hengyi
H
Zhao
Qiong
Q
Xie
Zhuibai
Z
Qiu
Hongzhuan
H
Chen
Hao
H
Wang
D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D019540:Area Under Curve; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002138:Calibration; D002626:Chemistry, Pharmaceutical / Q000379:methods; D002853:Chromatography, Liquid; D005260:Female; D005561:Formates / Q000737:chemistry; D008297:Male; D008621:Meptazinol / Q000031:analogs & derivatives* / Q000032:analysis / Q000493:pharmacokinetics; D051379:Mice; D048448:Phenylcarbamates / Q000032:analysis* / Q000737:chemistry / Q000493:pharmacokinetics*; D011786:Quality Control; D015203:Reproducibility of Results; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry; D013696:Temperature; D014018:Tissue Distribution
D005561:Formates; D048448:Phenylcarbamates; C000591387:meserine; C030544:formic acid; D008621:Meptazinol