Inhibition of P-glycoprotein leads to improved oral bioavailability of compound K, an anticancer metabolite of red ginseng extract produced by gut microflora

Zhen Yang, Jing Rong Wang, Tao Niu, Song Gao, Taijun Yin, Ming You, Zhi Hong Jiang, Ming Hu

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

Abstract

Ginsenosides are hydrolyzed extensively by gut microflora after oral administration, and their metabolites are pharmacologically active against lung cancer cells. In this study, we measured the metabolism of various ginsenosides by gut microflora and determined the mechanisms responsible for the observed pharmacokinetic behaviors of its active metabolite, Compound K (C-K). The results showed that biotransformation into C-K is the major metabolic pathway of ginsenosides after the oral administration of the red ginseng extract containing both protopanaxadiol and protopanaxatriol ginsenosides. Pharmacokinetic studies in normal mice showed that C-K exhibited low oral bioavailability. To define the mechanisms responsible for this low bioavailability, two P-glycoprotein (P-gp) inhibitors, verapamil and cyclosporine A, were used, and their presence substantially decreased C-K's efflux ratio in Caco-2 cells (from 26.6 to <3) and significantly increased intracellular concentrations (by as much as 40-fold). Similar results were obtained when transcellular transport of C-K was determined using multidrug resistance 1 (MDR1)-overexpressing Madin-Darby canine kidney II cells. In MDR1a/b(-/-) FVB mice, its plasma Cmaxand AUC0-24h were increased substantially by 4.0- and 11.7-fold, respectively. These increases appear to be due to slower elimination and faster absorption of C-K in MDR1a/b(-/-) mice. In conclusion, C-K is the major active metabolite of ginsenosides after microflora hydrolysis of primary ginsenosides in the red ginseng extract, and inhibition/deficiency of P-gp can lead to large enhancement of its absorption and bioavailability.

Original languageEnglish (US)
Pages (from-to)1538-1544
Number of pages7
JournalDrug Metabolism and Disposition
Volume40
Issue number8
DOIs
StatePublished - Aug 2012

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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