Chiral LC-MS/MS method development for the enhanced separation and determination of pranoprofen enantiomers and its application to a stereoselective pharmacokinetic study

Abstract

The objective of this study is to develop a quick and precise chiral liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) technology that operates in reversed phase mode. Following oral administration of 5.0 mg/kg rac-pranoprofen, the suggested approach was completely validated and successfully used to the stereoselective detection of pranoprofen enantiomers in rat plasma for the first time. Both the polysaccharide derivatized chiral stationary phase and a homemade β-cyclodextrin (β-CD) derivatized based chiral column were assessed. The latter one, a per-4-chlorophenylcarbamate-β-cyclodextrin bonded chiral stationary phase (CPCDP) made in our laboratory, allowed for the highly sensitive detection, relatively short retention time and complete separation (resolution 2.0) of the pranoprofen enantiomers. A solid phase extraction (SPE) procedure on C18 cartridge was optimized for the extraction of S-(+)-, R-(−)-pranoprofen and internal standard (S-(+)-ketoprofen, IS) from rat plasma in detail. Acetonitrile with 0.1 % formic acid in aqueous phase (60:40, v:v) at a flow rate of 0.6 mL/min was the ideal mobile phase condition. The outcome of pharmacokinetic study showed that the values of maximum plasma concentration (Cmax) and the area under plasma drug concentration–time curve to infinity (AUC0-∞) for S-(+)-pranoprofen were 1.79 and 1.90 times greater than R-(−)-isomer, respectively. Altogether, this work is the first to examine the stereospecific pharmacokinetics of pranoprofen enantiomers in vivo, whose data provided potential possibility for the development of pure isomer with superior pharmacological activity and safety to replace racemic application in the clinic.