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Enantioselective Plasma Pharmacokinetic Study of a Novel Anti- Sichistosomiasis Agent P96 in Rat by Liquid Chromatography-tandem Mass Spectrometry

[ Vol. 15 , Issue. 4 ]

Author(s):

Ran Meng, Danlu Zhang, Jianbo Ji, Lingyun Hu, Dequn Sun* and Haina Wang*   Pages 379 - 387 ( 9 )

Abstract:


Background: 2-Cyclopentanecarbonyl-1,2,3,6,7,11b-hexahydro-pyrazino[2,1- a]isoquinolin- 4-one (P96), was found to be a novel drug candidate with one chiral center to treat schistosomiasis caused by Schistosoma japonicum.

Objective: To study pharmacokinetic characteristics, a simple, rapid and sensitive liquid chromatography- tandem mass spectrometry (LC-MS/MS) method was developed and fully validated for the quantification analysis of P96 in rat plasma.

Methods: Chromatographic separation was performed on a C18 column with gradient eluted mobile phase composed of acetonitrile and water at a flow rate of 0.5 mL/min. Detection was performed on a triple-quadrupole tandem mass spectrometer using positive mode electrospray ionization in the multiple reactions monitoring (MRM) mode.

Results: Excellent linearity was observed in the range of 3-900 ng/mL with the lower limit of quantification of 3 ng/mL in rat plasma for P96. The intra- and inter-day precisions exhibited less than 6.6%. Mean recoveries ranged from 96.9% to 102.4%. This method was applied to investigate the enantioselective differences on the pharmacokinetics between (R,S)-P96 and its enantiomers in rats after oral administration. The enantioselective differences of (R)-P96, (S)-P96 and (R,S)-P96 were found and compared.

Conclusion: The established method was found to be accurate, precise, and sensitive and can be applied to investigate the stereoselective differences on pharmacokinetics between rac-P96 and its enantiomers.

Keywords:

P96, plasma, LC-MS/MS, pharmacokinetics, enantioselectivity, schistosomiasis.

Affiliation:

School of Pharmaceutical Sciences, Shandong University, Jinan 250012, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong Cancer Hospital Affiliated to Shandong University, Jinan 250117, Marine College, Shandong University at Weihai, Weihai 264209, School of Pharmaceutical Sciences, Shandong University, Jinan 250012

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