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Research ArticleArticle

Bioactivation Pathways of the Cannabinoid Receptor 1 Antagonist Rimonabant

Moa Andresen Bergström, Emre M. Isin, Neal Castagnoli Jr. and Claire E. Milne
Drug Metabolism and Disposition October 2011, 39 (10) 1823-1832; DOI: https://doi.org/10.1124/dmd.111.039412
Moa Andresen Bergström
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Emre M. Isin
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Neal Castagnoli Jr.
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Claire E. Milne
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Abstract

In the present work, the characterization of the biotransformation and bioactivation pathways of the cannabinoid receptor 1 antagonist rimonabant (Acomplia) is described. Rimonabant was approved in Europe in 2006 for the treatment of obesity but was withdrawn in 2008 because of a significant drug-related risk of serious psychiatric disorders. The aim of the present work is to characterize the biotransformation and potential bioactivation pathways of rimonabant in vitro in human and rat liver microsomes. The observation of a major iminium ion metabolite led us to perform reactive metabolite trapping, covalent binding to proteins, and time-dependent inhibition of cytochrome P450 3A4 studies. The major biotransformation pathways were oxidative dehydrogenation of the piperidinyl ring to an iminium ion, hydroxylation of the 3 position of the piperidinyl ring, and cleavage of the amide linkage. In coincubations with potassium cyanide, three cyanide adducts were detected. A high level of covalent binding of rimonabant in human liver microsomes was observed (920 pmol equivalents/mg protein). In coincubations with potassium cyanide and methoxylamine, the covalent binding was reduced by approximately 40 and 30%, respectively, whereas GSH had no significant effect on covalent binding levels. Rimonabant was also found to inhibit cytochrome P450 3A4 irreversibly in a time-dependent manner. In view of these findings, it is noteworthy that, to date, no toxicity findings related to the formation of reactive metabolites from rimonabant have been reported.

Footnotes

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

    doi:10.1124/dmd.111.039412.

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

  • ABBREVIATIONS:

    CB1r
    cannabinoid receptor 1
    ADR
    adverse drug reaction
    IADR
    idiosyncratic adverse drug reaction
    BFC
    7-benzyloxy-4-trifluoromethylcoumarin
    HLMs
    human liver microsomes
    KCN
    potassium cyanide
    LC
    liquid chromatography
    LSC
    liquid scintillation counting
    MS
    mass spectrometry
    RAD
    radiochemical detection
    RLMs
    rat liver microsomes
    TDI
    time-dependent inhibition.

  • Received March 10, 2011.
  • Accepted July 6, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (10)
Drug Metabolism and Disposition
Vol. 39, Issue 10
1 Oct 2011
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Research ArticleArticle

BIOACTIVATION PATHWAYS OF THE CB1r ANTAGONIST RIMONABANT

Moa Andresen Bergström, Emre M. Isin, Neal Castagnoli and Claire E. Milne
Drug Metabolism and Disposition October 1, 2011, 39 (10) 1823-1832; DOI: https://doi.org/10.1124/dmd.111.039412

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Research ArticleArticle

BIOACTIVATION PATHWAYS OF THE CB1r ANTAGONIST RIMONABANT

Moa Andresen Bergström, Emre M. Isin, Neal Castagnoli and Claire E. Milne
Drug Metabolism and Disposition October 1, 2011, 39 (10) 1823-1832; DOI: https://doi.org/10.1124/dmd.111.039412
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