RT Journal Article SR Electronic T1 20(S)-Ginsenoside Rh2 Noncompetitively Inhibits P-Glycoprotein In Vitro and In Vivo: A Case for Herb-Drug Interactions JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 2179 OP 2187 DO 10.1124/dmd.110.034793 VO 38 IS 12 A1 Jingwei Zhang A1 Fang Zhou A1 Xiaolan Wu A1 Yi Gu A1 Hua Ai A1 Yuanting Zheng A1 Yannan Li A1 Xiaoxuan Zhang A1 Gang Hao A1 Jianguo Sun A1 Ying Peng A1 Guangji Wang YR 2010 UL http://dmd.aspetjournals.org/content/38/12/2179.abstract AB P-glycoprotein (P-gp) is an ATP-dependent efflux transporter highly expressed in gastrointestinal tract and multidrug resistance tumor cells. Inhibition or induction of P-gp can cause drug-drug interactions and thus influence the effects of P-gp substrate drugs. Previous studies indicated that 20(S)-ginsenoside Rh2 [20(S)-Rh2] could synergistically enhance the anticancer effects of conventional chemotherapeutic agents at a nontoxic dose. The aim of present study was to investigate in vitro and in vivo whether 20(S)-Rh2 was a P-gp inhibitor and analyze the possible inhibitory mechanisms and potential herb-drug interactions. Results showed that in vitro, 20(S)-Rh2 significantly enhanced rhodamine 123 retention in cells and decreased the efflux ratio of digoxin, fexofenadine, and etoposide, which were comparable to the effects of the established P-gp inhibitor verapamil. However, the transport of 20(S)-Rh2 suggested that 20(S)-Rh2 was not a P-gp substrate. Furthermore, the inhibitory effect persisted for at least 3 h after removal of 20(S)-Rh2. Unlike P-gp substrates, 20(S)-Rh2 inhibited both basal and verapamil-stimulated P-gp ATPase activities. It also significantly decreased UIC2 binding fluorescence, a marker for conformational change of P-gp. In situ and in vivo experiments showed that 20(S)-Rh2 increased the area under the plasma concentration-time curve and maximum plasma concentration of digoxin, fexofenadine, and etoposide significantly without affecting terminal elimination half-time. Long-term treatment with 20(S)-Rh2 failed to affect intestinal P-gp expression in vitro and in vivo. In conclusion, 20(S)-Rh2 is a potent noncompetitive P-gp inhibitor, which indicates a potential herb-drug interaction when 20(S)-Rh2 is coadministered with P-gp substrate drugs. It could increase the absorption of P-gp substrate drugs without long-term induction of P-gp expression in rats.