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Vol. 302, Issue 1, 369-373, July 2002

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

Jean-Francois Marier , Pascal Vachon, Ari Gritsas, Jie Zhang, Jean-Pierre Moreau and Murray P. Ducharme

MDS Pharma Services, Montreal, Quebec, Canada (J.-F.M., A.G., J.Z., J.-P.M., M.P.D.); and Faculté de Pharmacie, University of Montreal, Montreal, Quebec, Canada (J.-F.M., P.V., M.P.D.)

Pharmacokinetics of trans-resveratrol in its aglycone (RESAGL) and glucuronide (RESGLU) 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 beta -cyclodextrin to intact rats. In addition, the enterohepatic recirculation of RESAGL and RESGLU was assessed in a linked-rat model. Multiple plasma and urine samples were collected and concentrations of RESAGL and RESGLU were determined using an electrospray ionization-liquid chromatography/tandem mass spectrometry method. After i.v. administration, plasma concentrations of RESAGL declined with a rapid elimination half-life (T1/2, 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 RESAGL (T1/2TER, 1.31 h). RESAGL and RESGLU also displayed sudden increases in plasma concentrations 4 to 8 h after oral administration, with T1/2TER of 1.48 and 1.58 h, respectively. RESAGL bioavailability was 38% and its exposure was approximately 46-fold lower than that of RESGLU (AUCinf, 7.1 versus 324.7 µmol·h/l). Enterohepatic recirculation was confirmed in the linked-rat model since significant plasma concentrations of RESAGL and RESGLU were observed in bile-recipient rats at 4 to 8 h. The percentages of the exposures of RESAGL and RESGLU 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 RESAGL is bioavailable and undergoes extensive first-pass glucuronidation, and that enterohepatic recirculation contributes significantly to the exposure of RESAGL and RESGLU in rats.

0022-3565/02/3021-0369$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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