RT Journal Article
SR Electronic
T1 Bioavailability of the Glucuronide and Sulfate Conjugates of Genistein and Daidzein in Breast Cancer Resistance Protein 1 Knockout Mice
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 2008
OP 2012
DO 10.1124/dmd.111.040881
VO 39
IS 11
A1 Ana I. Álvarez
A1 Fernando Vallejo
A1 Borja Barrera
A1 Gracia Merino
A1 Julio G. Prieto
A1 Francisco Tomás-Barberán
A1 Juan C. Espín
YR 2011
UL http://dmd.aspetjournals.org/content/39/11/2008.abstract
AB 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, the concentration of which was significantly increased (7- to 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 versus 4988 ± 508 in Bcrp1(−/−) mice after genistein administration (50 mg/kg b.wt.); 584.3 ± 90 in wild-type mice versus 4012 ± 612 in Bcrp1(−/−) after daidzein administration (50 mg/kg); and 926 ± 140 in wild-type mice versus 5174 ± 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.