Cancer chemotherapy and pharmacology
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Cancer Chemother. Pharmacol. · Apr 2002
P-glycoprotein inhibition by the multidrug resistance-reversing agent MS-209 enhances bioavailability and antitumor efficacy of orally administered paclitaxel.
Recent studies in humans and mice have demonstrated that intestinal P-glycoprotein plays a causative role in the limited absorption of orally administered paclitaxel. Multidrug resistance (MDR)-reversing agents, such as cyclosporin A and PSC 833, are known to increase the systemic exposure to orally administered paclitaxel by enhancing absorption in the intestinal tract and decreasing elimination via the biliary tract. In this study, we demonstrated that coadministration of the MDR-reversing agent MS-209, which is known to inhibit P-glycoprotein function by direct interaction, improved the bioavailability of orally administered paclitaxel and consequently enhanced its antitumor activity. ⋯ The present study suggests that coadministration of MS-209 may be a useful way to improve the bioavailability of drugs not suitable for oral administration due to elimination via the intestinal tract.