Stereoselective pharmacokinetic and metabolism studies of 20(S)- and 20(R)-ginsenoside Rg3 epimers in rat plasma by liquid chromatography-electrospray ionization mass spectrometry

• 3 Pairs of ginsenoside epimers were simultaneously detected by LC–MS/MS in MRM mode.
• Rg3 epimers shows stereoselective pharmacokinetic and metabolism behaviors in rats.
• 20(R)-Rg3 undergoes chiral inversion in rats, however 20(S)-Rg3 does not.

20(S)- and 20(R)-ginsenoside Rg3 are a pair of epimers which could be deglycosylated to ginsenoside Rh2 and protopanaxadiol (PPD) in vivo. To better understand the differences of pharmacokinetic parameters and metabolism behaviors of Rg3 epimers in rat plasma, a sensitive and specific liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS) method was developed and fully validated. This chromatographic method separate 20(S)-/20(R)-Rg3, 20(S)-/20(R)-Rh2 and 20(S)-/20(R)-PPD by gradient elution of 10 mM ammonium acetate solution (pH 5.0) and acetonitrile on a C18 column with a total run time of 15 min. 20(S)-protopanaxatriol (PPT) was used as internal standard, and multiple reaction monitoring (MRM) mode with negative electrospray ionization were performed. The lower limit of quantitations (LLOQs) were between 4.2 and 4.8 ng/ml, and the accuracies were between 91.7% and 112.2% with intra- and inter-day precisions less than 11.6%. This method was successfully applied to a pharmacokinetic study of intravenous and intra-gastric administration of 20(S)-Rg3 and 20(R)-Rg3 to rats. It has been found that both epimers can be deglycosylated to their corresponding chiral metabolites, i.e., Rh2 and PPD, with different extents. However, 20(R)-Rg3 underwent single direction chiral inversion to 20(S)-Rg3 in rats. Stereoselective pharmacokinetic parameters, metabolic degrees and chiral inversion extents of Rg3 epimers in rats were also discussed for the first time.

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