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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

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
Journal of Pharmacology and Experimental Therapeutics July 2002, 302 (1) 369-373; DOI: https://doi.org/10.1124/jpet.102.033340
Jean-Francois Marier
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Pascal Vachon
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Ari Gritsas
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Jie Zhang
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Jean-Pierre Moreau
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Murray P. Ducharme
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Abstract

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 β-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). RESAGLand RESGLU also displayed sudden increases in plasma concentrations 4 to 8 h after oral administration, withT1/2TER 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.

Footnotes

  • DOI: 10.1124/jpet.102.033340

  • Abbreviations:
    RESAGL
    resveratrol in its aglycone form
    RESGLU
    total glucuronide metabolites of resveratrol
    Ae0–12
    cumulative amount of drug excreted in urine from time 0 to 12 h
    AUC0–t
    area under the curve from time 0 to the last measurable plasma concentration
    AUCinf
    area under the curve extrapolated to infinity
    CL
    clearance
    CL/F
    oral clearance
    CL/Fm
    apparent clearance of metabolite
    Cmax
    maximum observed plasma concentration
    %ER
    percentage of the exposure due to enterohepatic recirculation
    ESI-LC/MS/MS
    electrospray ionization liquid chromatography tandem mass spectrometry
    MRT
    mean residence time
    T1/2
    apparent elimination half-life before enterohepatic recirculation was thought to occur
    T1/2TER
    terminal elimination half-life with enterohepatic recirculation
    Tmax
    time of maximum observed plasma concentration
    Varea/F
    apparent volume of distribution after oral administration
    Varea/Fm
    apparent volume of distribution of metabolite
    Vss
    total volume of distribution
    • Received January 18, 2002.
    • Accepted March 27, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 302 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 302, Issue 1
1 Jul 2002
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

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
Journal of Pharmacology and Experimental Therapeutics July 1, 2002, 302 (1) 369-373; DOI: https://doi.org/10.1124/jpet.102.033340

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

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
Journal of Pharmacology and Experimental Therapeutics July 1, 2002, 302 (1) 369-373; DOI: https://doi.org/10.1124/jpet.102.033340
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