Metabolism and disposition of resveratrol in the isolated perfused rat liver: role of Mrp2 in the biliary excretion of glucuronides.
In this study, the hepatic metabolism and transport system for resveratrol was examined in isolated perfused livers from Wistar and Mrp2-deficient TR(-) rats. Based on extensive metabolism to six glucuronides and sulfates (M1-M6), the hepatic extraction ratio and clearance of resveratrol was very high in Wistar and TR(-) rats (E: 0.998 vs. 0.999; Cl: 34.9 mL/min vs. 36.0 mL/min). However, biliary excretion and efflux of conjugates differs greatly in TR(-) rats. While cumulative biliary excretion of the glucuronides M1, M2, M3, and M5 dropped dramatically to 0-6%, their efflux into perfusate increased by 3.6-, 1.8-, 2.5-, and 1.5-fold. In contrast, biliary secretion of the sulfates M4 and M6 was partially maintained in the Mrp2-deficient rats (61% and 39%) with a concomitant decline of their efflux into perfusate by 33.2% and 78.1%. This indicates that Mrp2 exclusively mediates the biliary excretion of resveratrol glucuronides but only partly that of sulfates. Cumulative secretion of unconjugated resveratrol into bile of TR(-) rats was only reduced by 40%, and into perfusate by 19%, suggesting only a minor role of Mrp2 in resveratrol elimination. In summary, resveratrol was dose-dependently metabolized to several conjugates whereby the canalicular transporter Mrp2 selectively mediated the biliary excretion of glucuronides.
Maier-Salamon
Alexandra
A
Department of Clinical Pharmacy and Diagnostics, University of Vienna, A-1090 Vienna, Austria.
Hagenauer
Birigt
B
Reznicek
Gottfried
G
Szekeres
Thomas
T
Thalhammer
Theresia
T
Jäger
Walter
W
D000818:Animals; D001646:Bile / Q000378:metabolism*; D001682:Biological Availability; D020719:Glucuronides / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D026901:Membrane Transport Proteins / Q000502:physiology*; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000502:physiology*; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D000077185:Resveratrol; D013267:Stilbenes / Q000493:pharmacokinetics* / Q000494:pharmacology; D013448:Sulfobromophthalein / Q000378:metabolism; D013656:Taurocholic Acid / Q000378:metabolism
D020719:Glucuronides; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000077185:Resveratrol; D013267:Stilbenes; D013448:Sulfobromophthalein; D013656:Taurocholic Acid