pgp - publications

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1. PLoS One. 2012;7(4):e35768. Epub 2012 Apr 18.

Stereoselective regulations of p-glycoprotein by ginsenoside rh2 epimers and the
potential mechanisms from the view of pharmacokinetics.

Zhang J, Zhou F, Niu F, Lu M, Wu X, Sun J, Wang G.

Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University,
Nanjing, Jiangsu, China.

Chirality is an interesting topic and it is meaningful to explore the
interactions between chiral small molecules and stereoselective
biomacromolecules, with pre-clinical and clinical significances. We have
previously demonstrated that 20(S)-ginsenoside Rh2 is an effective P-glycoprotein
(P-gp) inhibitor in vitro and in vivo. Considering the stereochemistry of
ginsenoside Rh2, in our present study, the regulatory effects of 20(R)-Rh2 on
P-gp were assayed in vivo, and the differential regulations of P-gp by
ginsenoside Rh2 epimers in vivo were compared and studied. Results showed that
20(S)-Rh2 enhanced the oral absorption of digoxin in rats in a dose-dependent
manner; 20(R)-Rh2 at low dosage increased the oral absorption of digoxin, but
this effect diminished with elevated dosage of 20(R)-Rh2. Further studies
indicated stereoselective pharmacokinetic profiles and intestinal
biotransformations of Rh2 epimers. In vitro studies showed that Rh2 epimers and
their corresponding deglycosylation metabolites protopanaxadiol (Ppd) epimers all
exhibited stereoselective regulations of P-gp. In conclusion, in view of the in
vitro and in vivo dispositions of Rh2 and the regulations of P-gp by Rh2 and Ppd,
it is suggested that the P-gp regulatory effect of Rh2 in vivo actually is a
double actions of both Rh2 and Ppd, and the net effect is determined by the
relative balance between Rh2 and Ppd with the same configuration. Our study
provides new evidence of the chiral characteristics of P-gp, and is helpful to
elucidate the stereoselective P-gp regulation mechanisms of ginsenoside Rh2
epimers in vivo from a pharmacokinetic view.

PMID: 22530069 [PubMed - in process]