Everted rat intestinal sacs: a new model for the quantitation of P-glycoprotein mediated-efflux of anticancer agents.

P-Glycoprotein (p-gp) situated in the epithelium of the gastrointestinal tract is a recognised barrier limiting oral absorption of antitumour agents. Here we describe the rat everted gut sac as a new in vitro model for quantitation of p-gp-mediated efflux of anti-cancer agents using [3H]vinblastine, [14C] doxorubicin and verapamil as reference compounds. Tissue and serosal uptake of [3H]vinblastine was linear over 90 min (0.031 +/- 0.001 and 0.003 +/- 0.001 ng/mg protein/h respectively). [14C]Doxorubicin tissue accumulation was significantly lower; 0.006 +/- 0.001 ng/mg protein/h (p < 0.05) whereas serosal transfer was significantly higher 0.017 +/- 0.001 ng/mg protein/h (p < 0.05) than [3H]vinblastine. Addition of verapamil (40 ng/mL) increased significantly both tissue accumulation of [3H] vinblastine and [14C]doxorubicin (to 0.060 +/- 0.024 and 0.034 +/- 0.012 ng/mg protein/h respectively) and serosal transfer (to 0.006 +/- 0.002 and 0.023 +/- 0.001 ng/mg protein/h) (p < 0.05 in all cases). The reproducibility of this in vitro model suggests that the rat everted gut sac is a useful screening tool for studying transport of p-gp substrates and potential p-gp modifiers.