Abstract
P-glycoprotein (P-gp) is an ATP-dependent efflux transporter highly expressed in gastrointestinal tract and multi-drug 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)-Rh2 could synergistically enhance the anti-cancer effects of conventional chemotherapeutic agents at a non-toxic 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 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 UIC-2 binding fluorescence, a marker for conformational change of P-gp. In situ and in vivo experiments showed that 20(S)-Rh2 increased AUC and Cmax of digoxin, fexofenadine and etoposide significantly without affecting terminal elimination half-time. Long-term treatment of 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 a long-term induction of P-gp expression in rats.
- Received June 1, 2010.
- Accepted September 13, 2010.
- The American Society for Pharmacology and Experimental Therapeutics