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.
METHODS: RESULTS: The plasma concentration of [(3)H]
paclitaxel following
oral administration was significantly increased by coadministration of
MS-209 at 100 mg/kg in both rats and mice. In rats, the AUC of [(3)H]
paclitaxel following
oral administration was strikingly increased (1.9-fold) by coadministration of
MS-209, whereas the AUC of [(3)H]
paclitaxel following i.v. injection was slightly increased (1.3-fold) by
MS-209. The increase in apparent bioavailability of oral
paclitaxel due to
MS-209 was 1.4-fold. To demonstrate this enhancing action in vitro, we studied the influence of
MS-209 on the transport of [(3)H]
paclitaxel using Caco-2 cells, which is a well-known model of intestinal efflux. The transport of [(3)H]
paclitaxel across the Caco-2 monolayer was markedly inhibited in the presence of
MS-209, and the apparent K(i)of
MS-209 for the active transport of [(3)H]
paclitaxel was 0.4 microM. Moreover,
paclitaxel administered orally at 100 mg/kg per day with
MS-209 at 100 mg/kg per day showed significant antitumor activity in
B16 melanoma-bearing mice, whereas
paclitaxel administered orally alone at the same dose showed no antitumor activity. These results suggest that the coadministration of
MS-209 improved low systemic exposure to
paclitaxel through inhibition of
P-glycoprotein, which is involved in drug excretion via the intestinal tract, resulting in a clear antitumor activity of
paclitaxel administered orally.
CONCLUSION: 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.