Ginsenoside metabolites inhibit P-glycoprotein in vitro and in situ using three absorption models.

P-glycoprotein, an ATP-dependent transporter expressed in the gastrointestinal tract and tumor cells, mediates the efflux transport of multiple drugs. Inhibition or induction of P-glycoprotein by herbal ingredients can lead to herb-drug interactions and thus influence the activities of P-glycoprotein substrate drugs. The present study aimed to explore the effect of nine naturally occurring ginsenosides and their intestinal bacterial metabolites on P-glycoprotein-mediated transport. The results showed that three ginsenoside metabolites (CK, Ppd, and Ppt) formed by intestinal bacteria significantly enhanced rhodamine 123 retention in Caco-2 cells, increased the absorptive permeability of rhodamine 123, and decreased the efflux ratio of digoxin in two absorption models, which were comparable to the effects of the known P-glycoprotein inhibitor verapamil. However, the prototype ginsenosides such as Rb1, Rb2, and Re showed no inhibitory effect on P-glycoprotein activity. In situ intestinal perfusion experiments also showed that CK, Ppd, and Ppt increased the absorption rate constant and permeability coefficient of rhodamine 123. Long-term treatment with CK, Ppd, and Ppt had no effect on P-glycoprotein mRNA expression in Caco-2 cells. In conclusion, CK, Ppd, and Ppt are potent P-glycoprotein inhibitors, indicating an unpredictable herb-drug interaction when ginsenosides are coadministered orally with P-glycoprotein substrate drugs.