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Research ArticleArticle

Species Differences in the Biotransformation of an α4β2 Nicotinic Acetylcholine Receptor Partial Agonist: The Effects of Distinct Glucuronide Metabolites on Overall Compound Disposition

Christopher L. Shaffer, Mithat Gunduz, Tim F. Ryder and Thomas N. O'Connell
Drug Metabolism and Disposition February 2010, 38 (2) 292-301; DOI: https://doi.org/10.1124/dmd.109.030171
Christopher L. Shaffer
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Mithat Gunduz
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Tim F. Ryder
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Thomas N. O'Connell
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Abstract

The metabolism and disposition of (1R,5S)-2,3,4,5-tetrahydro-7-(trifluoromethyl)-1,5-methano-1H-3-benzazepine (1), an α4β2 nicotinic acetylcholine receptor partial agonist, was investigated in Sprague-Dawley rats and cynomolgus monkeys receiving (1R,5S)-2,3,4,5-tetrahydro-7-(trifluoromethyl)-1,5-methano-1H-4[14C]-3- benzazepine hydrochloride ([14C]1) orally. Although both species chiefly (≥62%) cleared 1 metabolically, species-specific dispositional profiles were observed for both 1 and total radioactivity. Radioactivity was excreted equally in the urine and feces of intact rats but largely (72%) in bile in bile duct-cannulated animals. In monkeys, radioactivity recoveries were 50-fold greater in urine than feces and minimal (<5%) in bile. Both species metabolized 1 similarly: four-electron oxidation to one of four amino acids or two lactams (minor) and glucuronide formation (major). In rats, the latter pathway predominantly formed an N-carbamoyl glucuronide (M6), exclusively present in bile (69% of dose), whereas in monkeys it afforded an N-O-glucuronide (M5), a minor biliary component (4%) but the major plasma (62%) and urinary (42%) entity. In rats, first-pass hepatic conversion of 1 to M6, which was confirmed in rat hepatocytes, and its biliary secretion resulted in the indirect enterohepatic cycling of 1 via M6 and manifested in double-humped plasma concentration-time curves and long t1/2 for both 1 and total radioactivity. In monkeys, in which only M5 was formed, double-humped plasma concentration-time curves were absent, and moderate t1/2 for both 1 and total radioactivity were observed. A seemingly subtle, yet critical, difference in the chemical structures of these two glucuronide metabolites considerably affected the overall disposition of 1 in rats versus monkeys.

Footnotes

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

    doi:10.1124/dmd.109.030171

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

  • P450
    cytochrome P450
    1
    (1R,5S)-2,3,4,5-tetrahydro-7-(trifluoromethyl)-1,5-methano-1H-3-benzazepine hydrochloride
    [14C]1
    (1R,5S)-2,3,4,5-tetrahydro-7-(trifluoromethyl)-1,5-methano-1H-4[14C]-3-benzazepine hydrochloride
    2
    (1R,5S)-2,3,4,5-tetrahydro-7-(trifluoromethyl)-1,5-methano-4-oxo-1H-3-benzazepine
    3
    (1R,5S)-2,3,4,5-tetrahydro-7-(trifluoromethyl)-1,5-methano-2-oxo-1H-3-benzazepine
    4
    (1R,5S)-2,3,4,5-tetrahydro-7-(trifluoromethyl)-1,5-methano-1H-3-benzazepine-3-carboxaldehyde
    PGRD
    Pfizer Global Research and Development
    RLM
    rat liver microsome
    MLM
    monkey liver microsome
    HPLC
    high-performance liquid chromatography
    LSC
    liquid scintillation counting
    LC/MS/MS
    liquid chromatography/tandem mass spectrometry
    RCF
    relative centrifugal force
    MRM
    multiple-reaction monitoring
    AUC
    area under the concentration-time curve
    kel
    elimination rate constant
    LC/MS/NMR
    liquid chromatography/mass spectrometry/nuclear magnetic resonance
    CID
    collision-induced dissociation
    EHC
    enterohepatic cycling
    FMO
    FAD-containing monooxygenase.

    • Received September 8, 2009.
    • Accepted November 6, 2009.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (2)
Drug Metabolism and Disposition
Vol. 38, Issue 2
1 Feb 2010
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Research ArticleArticle

Species Differences in the Biotransformation of an α4β2 Nicotinic Acetylcholine Receptor Partial Agonist: The Effects of Distinct Glucuronide Metabolites on Overall Compound Disposition

Christopher L. Shaffer, Mithat Gunduz, Tim F. Ryder and Thomas N. O'Connell
Drug Metabolism and Disposition February 1, 2010, 38 (2) 292-301; DOI: https://doi.org/10.1124/dmd.109.030171

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Research ArticleArticle

Species Differences in the Biotransformation of an α4β2 Nicotinic Acetylcholine Receptor Partial Agonist: The Effects of Distinct Glucuronide Metabolites on Overall Compound Disposition

Christopher L. Shaffer, Mithat Gunduz, Tim F. Ryder and Thomas N. O'Connell
Drug Metabolism and Disposition February 1, 2010, 38 (2) 292-301; DOI: https://doi.org/10.1124/dmd.109.030171
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