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Research ArticleArticle

Metabolism and Disposition of [14C]Brivanib Alaninate after Oral Administration to Rats, Monkeys, and Humans

Jiachang Gong, Jinping Gan, Janet Caceres-Cortes, Lisa J. Christopher, Vinod Arora, Eric Masson, Daphne Williams, Janice Pursley, Alban Allentoff, Michael Lago, Scott B. Tran and Ramaswamy A. Iyer
Drug Metabolism and Disposition May 2011, 39 (5) 891-903; DOI: https://doi.org/10.1124/dmd.110.037341
Jiachang Gong
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Jinping Gan
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Janet Caceres-Cortes
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Lisa J. Christopher
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Vinod Arora
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Eric Masson
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Daphne Williams
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Janice Pursley
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Alban Allentoff
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Michael Lago
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Scott B. Tran
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Ramaswamy A. Iyer
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Abstract

Brivanib [(R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[1,2,4]triazin-6-yloxy)propan-2-ol, BMS-540215] is a potent and selective dual inhibitor of vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) signaling pathways. Its alanine prodrug, brivanib alaninate [(1R,2S)-2-aminopropionic acid 2-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy]-1-methylethyl ester, BMS-582664], is currently under development as an oral agent for the treatment of cancer. This study describes the in vivo biotransformation of brivanib after a single oral dose of [14C]brivanib alaninate to intact rats, bile duct-cannulated (BDC) rats, intact monkeys, BDC monkeys, and humans. Fecal excretion was the primary route of elimination of drug-derived radioactivity in animals and humans. In BDC rats and monkeys, the majority of radioactivity was excreted in bile. Brivanib alaninate was rapidly and completely converted via hydrolysis to brivanib in vivo. The area under the curve from zero to infinity of brivanib accounted for 14.2 to 54.3% of circulating radioactivity in plasma in animals and humans, suggesting that metabolites contributed significantly to the total drug-related radioactivity. In plasma from animals and humans, brivanib was a prominent circulating component. All the metabolites that humans were exposed to were also present in toxicological species. On the basis of metabolite exposure and activity against VEGF and FGF receptors of the prominent human circulating metabolites, only brivanib is expected to contribute to the pharmacological effects in humans. Unchanged brivanib was not detected in urine or bile samples, suggesting that metabolic clearance was the primary route of elimination. The primary metabolic pathways were oxidative and conjugative metabolism of brivanib.

Footnotes

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

    doi:10.1124/dmd.110.037341.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    VEGFR
    vascular endothelial growth factor receptor
    FGFR
    fibroblast growth factor receptor
    BMS-540215
    (R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[1,2,4]triazin-6-yloxy)propan-2-ol
    BMS-582664
    (1R,2S)-2-aminopropionic acid 2-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy]-1-methylethyl ester
    ADME
    absorption, disposition, metabolism, and excretion
    BDC
    bile duct-cannulated
    GI
    gastrointestinal
    LC
    liquid chromatography
    MS
    mass spectroscopy
    HLM
    human liver microsomes
    UDPGA
    UDP-glucuronic acid trisodium salt
    DMSO
    dimethyl sulfoxide
    HPLC
    high-performance liquid chromatography
    MS/MS
    tandem mass spectrometry
    LSC
    liquid scintillation counting
    TRA
    total radioactivity
    ESI
    electrospray ionization
    MRM
    multiple reaction monitoring
    1-D
    one-dimensional
    2-D
    two-dimensional
    HMBC
    heteronuclear multiple-bond correlation spectroscopy
    AUC
    area under the concentration-time curve.

  • Received November 18, 2010.
  • Accepted January 31, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (5)
Drug Metabolism and Disposition
Vol. 39, Issue 5
1 May 2011
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Research ArticleArticle

Metabolism and Disposition of [14C]Brivanib Alaninate after Oral Administration to Rats, Monkeys, and Humans

Jiachang Gong, Jinping Gan, Janet Caceres-Cortes, Lisa J. Christopher, Vinod Arora, Eric Masson, Daphne Williams, Janice Pursley, Alban Allentoff, Michael Lago, Scott B. Tran and Ramaswamy A. Iyer
Drug Metabolism and Disposition May 1, 2011, 39 (5) 891-903; DOI: https://doi.org/10.1124/dmd.110.037341

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Research ArticleArticle

Metabolism and Disposition of [14C]Brivanib Alaninate after Oral Administration to Rats, Monkeys, and Humans

Jiachang Gong, Jinping Gan, Janet Caceres-Cortes, Lisa J. Christopher, Vinod Arora, Eric Masson, Daphne Williams, Janice Pursley, Alban Allentoff, Michael Lago, Scott B. Tran and Ramaswamy A. Iyer
Drug Metabolism and Disposition May 1, 2011, 39 (5) 891-903; DOI: https://doi.org/10.1124/dmd.110.037341
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