Metabolism and Disposition of Resveratrol in the Isolated Perfused Rat Liver: Role of Mrp2 in the Biliary Excretion of Glucuronides

• Published in: Journal of pharmaceutical sciences Vol. 97; no. 4; pp. 1615 - 1628
• Main Authors: Maier‐Salamon, Alexandra, Hagenauer, Birigt, Reznicek, Gottfried, Szekeres, Thomas, Thalhammer, Theresia, Jäger, Walter
• Format: Journal Article
• Language: English
• Published: Hoboken Elsevier Inc 01.04.2008; Wiley Subscription Services, Inc., A Wiley Company; Wiley; American Pharmaceutical Association
• Subjects: Animals; Bile - metabolism; biliary excretion; Biological and medical sciences; Biological Availability; General pharmacology; Glucuronides - metabolism; hepatic clearance; hepatic metabolism; HPLC; Liver - metabolism; Male; Medical sciences; Membrane Transport Proteins - physiology; multidrug resistance-associated proteins; Multidrug Resistance-Associated Proteins - physiology; Perfusion; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Rats; Rats, Wistar; resveratrol; Stilbenes - pharmacokinetics; Stilbenes - pharmacology; Sulfobromophthalein - metabolism; Taurocholic Acid - metabolism; hepatic clearance; biliary excretion; multidrug resistance‐associated proteins; resveratrol; HPLC; hepatic metabolism; Excretion; Pharmaceutical technology; Rat; Liver; Rodentia; HPLC chromatography; Clearance; Antioxidant; Metabolism; Stilbene derivatives; Glucuroconjugate; Protein; Isolated organ; Vertebrata; Mammalia; Animal; Multiple resistance; Resveratrol; multidrug resistance-associated proteins; Pharmacokinetics
• ISSN: 0022-3549; 1520-6017
• 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. © 2007 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:1615–1628, 2008