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Research ArticleArticle

The Disposition, Metabolism, and Pharmacokinetics of a Selective Metabotropic Glutamate Receptor Agonist in Rats and Dogs

Jason T. Johnson, Edward L. Mattiuz, Sylvia H. Chay, Jennifer L. Herman, William J. Wheeler, Kelem Kassahun, Steven P. Swanson and Diane L. Phillips
Drug Metabolism and Disposition January 2002, 30 (1) 27-33; DOI: https://doi.org/10.1124/dmd.30.1.27
Jason T. Johnson
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Edward L. Mattiuz
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Sylvia H. Chay
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Jennifer L. Herman
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William J. Wheeler
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Kelem Kassahun
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Steven P. Swanson
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Diane L. Phillips
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Abstract

Compound LY354740 [(+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid], an analog of glutamic acid, is a selective group 2 metabotropic glutamate receptor agonist in clinical development for the treatment of anxiety. Studies have been conducted to characterize the absorption, disposition, metabolism, and excretion of LY354740 in rats and dogs after intravenous bolus or oral administration. Plasma concentrations of LY354740 were measured using a validated gas chromatography/mass spectrometry assay. In rats, LY354740 demonstrated linear pharmacokinetics after oral administration from 30 to 1000 mg/kg. The oral bioavailability of LY354740 was approximately 10% in rats and 45% in dogs. In the dog, food decreased the mean area under the plasma concentration-time curve value by approximately 34%, hence, decreasing the oral bioavailability of the compound. Excretion studies in both rats and dogs indicate that the absorbed drug is primarily eliminated via renal excretion. In addition, tissue distribution in rats showed that the highest levels of radioactivity were in the kidney and gastrointestinal tract, which is consistent with the excretion studies. Metabolism of LY354740 was evaluated in vitro using rat and dog liver microsomes and rat liver slices. In addition, urine and fecal samples from rat and dog excretion studies were profiled using HPLC with radio-detection. These evaluations indicated that neither rats nor dogs metabolized LY354740. In summary, LY354740 is poorly absorbed in rats, moderately absorbed in dogs, and rapidly excreted as unchanged drug in the urine.

Footnotes

  • Abbreviations used are::
    LY354740
    (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid
    LSN338771
    2-amino-6-(2-caboxyethyl)-bicyclo[3.1.0]hexane-2-carboxylic acid
    mGlu
    metabotropic glutamate
    GC/MS
    gas chromatography/mass spectrometry
    HPLC
    high-performance liquid chromatography
    QWBA
    quantitative whole-body autoradiography
    BQL
    below quantitation limit
    AUC
    area under the plasma concentration versus time curve
    Cmax
    maximum plasma concentration
    Tmax
    time to reach maximum plasma concentration
    ke
    elimination rate constant
    MRT
    mean residence time
    Vdss
    volume of distribution at steady state
    VdB
    apparent volume of distribution
    • Received April 10, 2001.
    • Accepted July 18, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 30 (1)
Drug Metabolism and Disposition
Vol. 30, Issue 1
1 Jan 2002
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Research ArticleArticle

The Disposition, Metabolism, and Pharmacokinetics of a Selective Metabotropic Glutamate Receptor Agonist in Rats and Dogs

Jason T. Johnson, Edward L. Mattiuz, Sylvia H. Chay, Jennifer L. Herman, William J. Wheeler, Kelem Kassahun, Steven P. Swanson and Diane L. Phillips
Drug Metabolism and Disposition January 1, 2002, 30 (1) 27-33; DOI: https://doi.org/10.1124/dmd.30.1.27

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Research ArticleArticle

The Disposition, Metabolism, and Pharmacokinetics of a Selective Metabotropic Glutamate Receptor Agonist in Rats and Dogs

Jason T. Johnson, Edward L. Mattiuz, Sylvia H. Chay, Jennifer L. Herman, William J. Wheeler, Kelem Kassahun, Steven P. Swanson and Diane L. Phillips
Drug Metabolism and Disposition January 1, 2002, 30 (1) 27-33; DOI: https://doi.org/10.1124/dmd.30.1.27
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