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

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 C(max) and AUC(0-24h) 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.