title: Everted rat intestinal sacs: a new model for the quantitation of P-glycoprotein mediated-efflux of anticancer agents.
abstract: 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.
authors.affiliation: Centre for Polymer Therapeutics, School of Pharmacy, University of London, U.K.
authors.forename: B
authors.initials: B
authors.lastname: Carreño-Gómez
authors.forename: R
authors.initials: R
authors.lastname: Duncan
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000378:metabolism* / Q000494:pharmacology; D066298:In Vitro Techniques; D007421:Intestine, Small / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014700:Verapamil / Q000378:metabolism / Q000494:pharmacology; D014747:Vinblastine / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D002121:Calcium Channel Blockers; D014747:Vinblastine; D004317:Doxorubicin; D014700:Verapamil