Metabolism and disposition of resveratrol in the isolated perfused rat liver: role of Mrp2 in the biliary excretion of glucuronides

J Pharm Sci. 2008 Apr;97(4):1615-28. doi: 10.1002/jps.21057.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bile / metabolism*
  • Biological Availability
  • Glucuronides / metabolism*
  • Liver / metabolism*
  • Male
  • Membrane Transport Proteins / physiology*
  • Multidrug Resistance-Associated Protein 2
  • Multidrug Resistance-Associated Proteins / physiology*
  • Perfusion
  • Rats
  • Rats, Wistar
  • Resveratrol
  • Stilbenes / pharmacokinetics*
  • Stilbenes / pharmacology
  • Sulfobromophthalein / metabolism
  • Taurocholic Acid / metabolism


  • Glucuronides
  • Membrane Transport Proteins
  • Multidrug Resistance-Associated Protein 2
  • Multidrug Resistance-Associated Proteins
  • Stilbenes
  • Sulfobromophthalein
  • Taurocholic Acid
  • Resveratrol