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1. Drug Metab Dispos. 2012 May 14. [Epub ahead of print]

Inhibition of P-glycoprotein Leads to Improved Oral Bioavailability of Compound
K, an Anti-cancer Metabolite of Red Ginseng Extract Produced by Gut Microflora.

Yang Z, Wang JR, Niu T, Gao S, Yin T, Jiang ZH, You M, Hu M.

1 University of Houston;

Ginsenosides are extensively hydrolyzed 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 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 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-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 less than 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 MDR1-overexpressing MDCKII cells. In MDR1a/b(-/-) FVB mice, its plasma
C(max) and AUC0(-24h) were substantially increased, 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.

PMID: 22584255 [PubMed - as supplied by publisher]