TY - JOUR T1 - Bioavailability of the Glucuronide and Sulfate Conjugates of Genistein and Daidzein in Bcrp1 Knockout Mice JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.111.040881 SP - dmd.111.040881 AU - Ana I Alvarez AU - Fernando Vallejo AU - Borja Barrera AU - Gracia Merino AU - Julio G Prieto AU - Francisco Tomas-Barberan AU - Juan C Espin Y1 - 2011/08/09 UR - http://dmd.aspetjournals.org/content/early/2011/08/09/dmd.111.040881.abstract N2 - The dietary polyphenols genistein and daidzein are potent effectors of biological processes. The plasma profile of both isoflavones is governed by the presence of phase II conjugates, mainly glucuronides and sulfates. Breast cancer resistance protein, (ABCG2/BCRP), interacts with genistein and daidzein, which are among the natural substrates of the transporter and competitively inhibit ABCG2-mediated drug efflux. ABCG2/BCRP can also transport glucuronide and sulfate conjugates. In this study we analyzed the plasma levels of aglycones and derived conjugated metabolites, glucuronides and sulfates, after intragastric administration of these isoflavones to wild-type and Bcrp1(-/-) knockout mice. The results show that overall plasmatic profile is mainly governed by sulfate and glucuronide derivatives whose concentration was significantly increased (7-10 fold) in Bcrp1(-/-) mice. The total AUC h nM (0-180 min), as the sum of aglycones, glucuronides and sulfates, was 901±207 in wild-type mice vs 4,988±508 in Bcrp1(-/-) mice after genistein administration (50 mg/kg body weight); 584.3±90 in wild-type mice vs 4,012±612 in Bcrp1(-/-) after daidzein administration (50 mg/kg) and 926±140 in wild-type mice vs 5,174±696 in Bcrp1(-/-) after genistein+daidzein administration (25+25 mg/kg). Therefore, our results indicate a direct and conclusive Bcrp1 efflux action on phase II metabolites of these isoflavones in vivo, and suggest a possible novel concept for ABCG2/BCRP as part of metabolism-driven efflux transport of these conjugates. ER -