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Research ArticleArticle

In Vivo-Formed versus Preformed Metabolite Kinetics of trans-Resveratrol-3-sulfate and trans-Resveratrol-3-glucuronide

Satish Sharan, Otito F. Iwuchukwu, Daniel J. Canney, Cheryl L. Zimmerman and Swati Nagar
Drug Metabolism and Disposition October 2012, 40 (10) 1993-2001; DOI: https://doi.org/10.1124/dmd.112.046417
Satish Sharan
Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, Pennsylvania (S.S., O.F.I., D.J.C., S.N.); and Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota (C.L.Z.)
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Otito F. Iwuchukwu
Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, Pennsylvania (S.S., O.F.I., D.J.C., S.N.); and Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota (C.L.Z.)
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Daniel J. Canney
Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, Pennsylvania (S.S., O.F.I., D.J.C., S.N.); and Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota (C.L.Z.)
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Cheryl L. Zimmerman
Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, Pennsylvania (S.S., O.F.I., D.J.C., S.N.); and Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota (C.L.Z.)
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Swati Nagar
Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, Pennsylvania (S.S., O.F.I., D.J.C., S.N.); and Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota (C.L.Z.)
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This article has a correction. Please see:

  • Correction to “In Vivo-Formed versus Preformed Metabolite Kinetics of trans-Resveratrol-3-sulfate and trans-Resveratrol-3-glucuronide” - December 01, 2012

Abstract

Metabolites in safety testing have gained a lot of attention recently. Regulatory agencies have suggested that the kinetics of preformed and in vivo-formed metabolites are comparable. This subject has been a topic of debate. We have compared the kinetics of in vivo-formed with preformed metabolites. trans-3,5,4′-Trihydroxystilbene [trans-resveratrol (RES)] and its two major metabolites, resveratrol-3-sulfate (R3S) and resveratrol-3-glucuronide (R3G) were used as model substrates. The pharmacokinetics (PK) of R3S and R3G were characterized under two situations. First, the pharmacokinetics of R3S and R3G were characterized (in vivo-formed metabolite) after administration of RES. Then, synthetic R3S and R3G were administered (preformed metabolite) and their pharmacokinetics were characterized. PK models were developed to describe the data. A three-compartment model for RES, a two-compartment model for R3S (preformed), and an enterohepatic cycling model for R3G (preformed) was found to describe the data well. These three models were further combined to build a comprehensive PK model, which was used to perform simulations to predict in vivo-formed metabolite kinetics. Comparisons were made between in vivo-formed and preformed metabolite kinetics. Marked differences were observed in the kinetics of preformed and in vivo-formed metabolites.

Footnotes

  • This work was supported in part by the National Institutes of Health National Cancer Institute [Grants R03-CA133943, R03-CA159389].

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    http://dx.doi.org/10.1124/dmd.112.046417.

  • ABBREVIATIONS:

    MIST
    drug metabolites in safety testing
    PK
    pharmacokinetics
    R3S
    trans-resveratrol-3-sulfate
    R3G
    trans-resveratrol-3-O-glucuronide
    RES
    trans-3,5,4′-trihydroxystilbene
    R4′G
    trans-resveratrol-4′-O-glucuronide
    R4′S
    trans-resveratrol-4′-sulfate
    i.a.
    intra-arterial administration
    AUC
    area under the plasma concentration-time curve
    LC-MS/MS
    liquid chromatography-tandem mass spectrometry
    APAP
    acetaminophen
    IS
    internal standard
    LOQ
    limit of quantitation
    MRT
    mean residence time
    Cl
    clearance
    CV
    coefficient of variation.

  • Received April 23, 2012.
  • Accepted July 17, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (10)
Drug Metabolism and Disposition
Vol. 40, Issue 10
1 Oct 2012
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Research ArticleArticle

IN VIVO-FORMED VERSUS PREFORMED METABOLITE KINETICS

Satish Sharan, Otito F. Iwuchukwu, Daniel J. Canney, Cheryl L. Zimmerman and Swati Nagar
Drug Metabolism and Disposition October 1, 2012, 40 (10) 1993-2001; DOI: https://doi.org/10.1124/dmd.112.046417

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Research ArticleArticle

IN VIVO-FORMED VERSUS PREFORMED METABOLITE KINETICS

Satish Sharan, Otito F. Iwuchukwu, Daniel J. Canney, Cheryl L. Zimmerman and Swati Nagar
Drug Metabolism and Disposition October 1, 2012, 40 (10) 1993-2001; DOI: https://doi.org/10.1124/dmd.112.046417
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