Metabolism and Disposition of Resveratrol in Rats: Extent of Absorption, Glucuronidation, and Enterohepatic Recirculation Evidenced by a Linked-Rat Model

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 302; no. 1; pp. 369 - 373
• Main Authors: Marier, Jean-Francois, Vachon, Pascal, Gritsas, Ari, Zhang, Jie, Moreau, Jean-Pierre, Ducharme, Murray P
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.07.2002
• Subjects: Animals; Antineoplastic Agents, Phytogenic - metabolism; Antineoplastic Agents, Phytogenic - pharmacokinetics; Area Under Curve; Bile - metabolism; Biotransformation; Enterohepatic Circulation; Glucuronides - metabolism; Intestinal Absorption; Male; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes - metabolism; Stilbenes - pharmacokinetics; Tissue Distribution
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.102.033340

Pharmacokinetics of trans- resveratrol in its aglycone (RES AGL ) and glucuronide (RES GLU ) forms were studied following intravenous (15 mg/kg i.v.) and oral (50 mg/kg p.o.) administration of trans- resveratrol in a solution of β-cyclodextrin to intact rats. In addition, the enterohepatic recirculation of RES AGL and RES GLU was assessed in a linked-rat model. Multiple plasma and urine samples were collected and concentrations of RES AGL and RES GLU were determined using an electrospray ionization-liquid chromatography/tandem mass spectrometry method. After i.v. administration, plasma concentrations of RES AGL declined with a rapid elimination half-life ( T 1/2 , 0.13 h), followed by sudden increases in plasma concentrations 4 to 8 h after drug administration. These plasma concentrations resulted in a significant prolongation of the terminal elimination half-life of RES AGL ( T 1/2TER , 1.31 h). RES AGL and RES GLU also displayed sudden increases in plasma concentrations 4 to 8 h after oral administration, with T 1/2TER of 1.48 and 1.58 h, respectively. RES AGL bioavailability was 38% and its exposure was approximately 46-fold lower than that of RES GLU (AUC inf , 7.1 versus 324.7 μmol·h/l). Enterohepatic recirculation was confirmed in the linked-rat model since significant plasma concentrations of RES AGL and RES GLU were observed in bile-recipient rats at 4 to 8 h. The percentages of the exposures of RES AGL and RES GLU that were due to enterohepatic recirculation were 24.7 and 24.0%, respectively. The fraction of drug excreted in the urine over a period of 12 h was negligible. These results confirm that RES AGL is bioavailable and undergoes extensive first-pass glucuronidation, and that enterohepatic recirculation contributes significantly to the exposure of RES AGL and RES GLU in rats.