The intestinal absorption of the
flavonoid quercetin in rats is limited by the secretion of glucuronidated metabolites back into the gut lumen. The objective of this study was to determine the role of the intestinal efflux transporters
breast cancer resistance
protein (Bcrp1)/Abcg2 and
multidrug resistance-associated protein 2 (Mrp2)/Abcc2. To study the possible involvement of Mrp2, we compared intestinal uptake of
quercetin-3-glucoside between control and Mrp2-deficient rats, using an in situ intestinal perfusion system. The contribution of Bcrp1 was determined using the specific inhibitor
fumitremorgin C (
FTC) in Mrp2-deficient rats. Furthermore, vectorial transport of
quercetin was studied in Madin-Darby canine kidney (MDCK)II cells transfected with either human MRP2 or murine Bcrp1. In these MDCKII cells, we showed an efficient efflux-directed transport of
quercetin by mouse Bcrp1, whereas in control and MRP2-transfected cells no vectorial transport of
quercetin was observed. In Mrp2-deficient rats, intestinal uptake of
quercetin from
quercetin-3-glucoside, efflux of
quercetin glucuronides to the gut lumen, and plasma concentration of
quercetin were similar to that in control rats. When intestinal Bcrp1 was inhibited by
FTC in Mrp2-deficient rats, total plasma concentrations of
quercetin and its methylated metabolite
isorhamnetin after 30 min of perfusion were more than twice that of controls (12.3 +/- 1.5 versus 5.6 +/- 1.3 muM; p < 0.01), whereas uptake of free
quercetin from the intestinal lumen was not affected. Instead, inhibition of Bcrp1 lowered the efflux of
quercetin glucuronides into the perfusion fluid by approximately 4-fold. In conclusion, Bcrp1 limits net intestinal absorption of
quercetin by pumping
quercetin glucuronides back into the lumen.