Polymeric exciplents able to overcome p-glycoprotein in vitro: promotion of (~3H) vinblastine oral bioavailability

摘要

P-Glycoprotein (p-gp) is a 170-180 KDa plasma membrane-localised glycoprotein responsible multidrug resistance in tumour cells~1. P-gp is also localised along the gastrointestinal (GI) tract, particularly in the small intestine and colon~1, and it is an important factor contributing to the poor oral bioavailability of many natural product drugs including the anticancer agents vinblastine, doxorubicin and paclitaxel. Although severla low molecular weight compounds have been identified which can inhibit p-gp~2 (e.g. verapamil), their intrinsic toxicity, particularly when co-administered with other pharmacologically active agents, limits their potential for use in formulations designed to increase oral bioavailability. There is thus a need to identify novel p-gp inhibitors that are not toxic systemically and can be suitably incorporated in commercial formulations.