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Research ArticleArticle

Disposition and Metabolism of [14C]SB-649868, an Orexin 1 and 2 Receptor Antagonist, in Humans

Cecilia Renzulli, Mike Nash, Mark Wright, Steven Thomas, Stefano Zamuner, Mario Pellegatti, Paolo Bettica and Gary Boyle
Drug Metabolism and Disposition February 2011, 39 (2) 215-227; DOI: https://doi.org/10.1124/dmd.110.035386
Cecilia Renzulli
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Mike Nash
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Mark Wright
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Steven Thomas
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Stefano Zamuner
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Mario Pellegatti
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Paolo Bettica
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Gary Boyle
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This article has a correction. Please see:

  • Correction to “Disposition and Metabolism of [14C]SB-649868, an Orexin 1 and 2 Receptor Antagonist, in Humans” - June 01, 2011

Abstract

N-[[(2S)-1-[[5-(4-fluorophenyl)-2-methyl-4-thiazolyl]carbonyl]-2-piperidinyl]methyl]-4-benzofurancarboxamide (SB-649868) is a novel orexin 1 and 2 receptor antagonist under development for insomnia treatment. The disposition of [14C]SB-649868 was determined in eight healthy male subjects using an open-label study design after a single oral dose of 30 mg. Blood, urine, and feces were collected at frequent intervals after dosing, and samples were analyzed by high-performance liquid chromatography-mass spectrometry coupled with off-line radiodetection for metabolite profiling and characterization. NMR spectroscopy was also used to further characterize certain metabolites. Elimination of drug-related material was almost complete over a 9-day period, occurring principally via the feces (79%), whereas urinary excretion accounted only for 12% of total radioactivity. Mean apparent half-life (t1/2) of plasma radioactivity was notably longer (39.3 h), with respect to that of unchanged SB-649868 (4.8 h), suggesting the presence of more slowly cleared metabolites. SB-649868 and an unusual hemiaminal metabolite, M98 (2-[((2S)-1-{[5-(4-fluorophenyl)-2-methyl-1,3-thiazol-4-yl]carbonyl}-2-piperidinyl)methyl]-3,5-dihydroxy-3,4-dihydro-1(2H)-isoquinolinone; GSK2329163), resulting from oxidation of the benzofuran ring and subsequent rearrangement, were the principal circulating components in plasma extracts. Two additional minor metabolites were also observed: a benzofuran ring-opened carboxylic acid M25 ([2-({[((2S)-1-{[5-(4-fluorophenyl)-2-methyl-1,3-thiazol-4-yl]carbonyl}-2-piperidinyl)methyl]amino}carbonyl)-6-hydroxyphenyl]acetic acid; GSK2329158) and an amine metabolite (M8). SB-649868 was extensively metabolized, and only negligible amounts were excreted unchanged. The principal route of metabolism was via oxidation of the benzofuran ring with the resultant M25 being the principal metabolite in excreta, representing at least 12% of the administered dose across urine and feces.

Footnotes

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

    doi:10.1124/dmd.110.035386.

  • ABBREVIATIONS:

    SB-649868
    N-[[(2S)-1-[[5-(4-fluorophenyl)-2-methyl-4-thiazolyl]carbonyl]-2-piperidinyl]methyl]-4-benzofurancarboxamide
    OX
    orexin
    AUC
    area under the plasma concentration-time curve
    HPLC
    high-performance liquid chromatography
    LSC
    liquid scintillation counting
    MS/MS
    tandem mass spectrometry
    QC
    quality control
    MS
    mass spectrometry
    M98 (GSK2329163)
    2-[((2S)-1-{[5-(4-fluorophenyl)-2-methyl-1,3-thiazol-4-yl]carbonyl}-2-piperidinyl)methyl]-3,5-dihydroxy-3,4-dihydro-1(2H)-isoquinolinone
    M25 (GSK2329158)
    [2-({[((2S)-1-{[5-(4-fluorophenyl)-2-methyl-1,3-thiazol-4-yl]carbonyl}-2-piperidinyl)methyl]amino}carbonyl)-6-hydroxyphenyl]acetic acid.

  • Received July 11, 2010.
  • Accepted November 2, 2010.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (2)
Drug Metabolism and Disposition
Vol. 39, Issue 2
1 Feb 2011
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Research ArticleArticle

Disposition and Metabolism of [14C]SB-649868, an Orexin 1 and 2 Receptor Antagonist, in Humans

Cecilia Renzulli, Mike Nash, Mark Wright, Steven Thomas, Stefano Zamuner, Mario Pellegatti, Paolo Bettica and Gary Boyle
Drug Metabolism and Disposition February 1, 2011, 39 (2) 215-227; DOI: https://doi.org/10.1124/dmd.110.035386

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Research ArticleArticle

Disposition and Metabolism of [14C]SB-649868, an Orexin 1 and 2 Receptor Antagonist, in Humans

Cecilia Renzulli, Mike Nash, Mark Wright, Steven Thomas, Stefano Zamuner, Mario Pellegatti, Paolo Bettica and Gary Boyle
Drug Metabolism and Disposition February 1, 2011, 39 (2) 215-227; DOI: https://doi.org/10.1124/dmd.110.035386
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