Enhanced oral bioavailability of paclitaxel by concomitant use of absorption enhancers and P-glycoprotein inhibitors in rats

摘要

Paclitaxel (PCT) is a cytotoxic agent with a broad antineoplastic activity. IV formulation of PCT causes hypersensitivity reactions in some patients and oral administration is an alternative to decrease the side effects. PCT is not orally available because of low solubility, lack of intestinal permeability, and efflux by pumps in intestinal wall. PCT solution in cremophor EL: ethanol (100 mg/kg) was administered orally to rats after pre-treatment by mefenamic acid, ibuprofen, verapamil, cyclosporine, and verapamilzibuprofen in individual groups. Ibuprofen presented positive effect on intestinal permeation of PCT. Cmax and area under the serum concentration versus time curve (AUC) after pre-treatment by ibuprofen was decreased when the oral dose of PCT was decreased to 50 and 25 mg/kg, while dose-blood concentration relationship was nonlinear. Rise in oral bioavailability of PCT after pre-treatment by cyclosporine was lower than ibuprofen. It seems that by using ibuprofen in concomitant with potent P-gp inhibitors before PCT solution, oral delivery of PCT could be promising.