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. (C) 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:1615-1628, 2008.