Polymeric excipients able to overcome p-glycoprotein in vivo:promotion of anticancer activity of doxorubicin administered orally.

摘要

The presence of p-glycoprotein (p-gp) in the GI tract, especially in the small intestine and colon~1, contributes to the poor bioavailability of many natural product drugs (including the anticancer agents vinblastine and doxorubicin). This may also lead to an inherent resistance to GI cancers to treatment by chemotherapy. Previously we have shown that low molecular weight inhibitors such as verapamil will block p-gp efflux of (~3H) vinblastine in the everted rat intestinal model in vitro~2. However such low molecular weight compounds have major disadvantages for commercial development as their co-administration leads to unacceptable toxicity in the clinic~1. Polymeric excipients such as alginates (ascophyllum: high in mannuronic acid, and flavicans: high in guluronic acid), xanthan and gellan gum as well as the surfactant polidocanol, increased the transfer of (~3H) vinblastine across the everted gut sac in vitro~2. Therefore, here the potential of these polymers to enhance oral bioavailability of (~3H) vinblastine and to promote doxorubicin antitumor activity (normally inactive orally) has been studied.