Stereoselective pharmacokinetics of 25-methoxyl-dammarane-3β,12β,20-triol and its active demethyl-metabolite epimers in rats after oral and intravenous administration

Stereoselectivity of ginsenosides produced from the stereogenic carbon-20 has been proved to be closely related to drug action including pharmacodynamics and pharmacokinetics. 25-Methoxydammarane-3,12,20-triol (25-OCH3-PPD) and 25-hydoxyprotopanaxadiol (25-OH-PPD) are novel protopanaxadiol-type (PPD) sapogenins. 25-OH-PPD was also the in vivo bioactive demethyl-metabolite of 25-OCH3-PPD. The study aimed to investigate the influence of 20(R/S)-configuration on the pharmacokinetics of 20(R/S)-25-OCH3-PPD epimers and 20(R/S)-25-OH-PPD epimers. When rats were given 20(R/S)-25-OCH3-PPD epimers intravenously, the pharmacokinetic profiles of both epimers of 25-OCH3-PPD were similar, while the pharmacokinetic behaviors of their demethyl-metabolites were obviously different. After rats received an oral dose of 20(R/S)-25-OCH3-PPD epimers, the C-max and AUC values of 20(S)-25-OCH3-PPD were at least 100 times higher than those of 20(R)-25-OCH3-PPD. Stereoselective pharmacokinetics of 25-OH-PPD was observed in rats after i.v. and i.g. administration of 20(R/S)-25-OH-PPD epimers. In vitro metabolic kinetics results indicated that faster hepatic metabolism of R-epimer should be one of the crucial factors accounting for the stereospecific pharmacokinetics of 25-OCH3-PPD and 25-OH-PPD epimers. (C) 2016 Elsevier B.V. All rights reserved.