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Keywords:

  • resveratrol;
  • hepatic metabolism;
  • hepatic clearance;
  • biliary excretion;
  • multidrug resistance-associated proteins;
  • HPLC

Abstract

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