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Research ArticleArticle

P450-Based Drug-Drug Interactions of Amiodarone and its Metabolites: Diversity of Inhibitory Mechanisms

Matthew G. McDonald, Nicholas T. Au and Allan E. Rettie
Drug Metabolism and Disposition November 2015, 43 (11) 1661-1669; DOI: https://doi.org/10.1124/dmd.115.065623
Matthew G. McDonald
Department of Medicinal Chemistry, University of Washington, Seattle, Washington (M.G.M., N.T.A., A.E.R.)
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Nicholas T. Au
Department of Medicinal Chemistry, University of Washington, Seattle, Washington (M.G.M., N.T.A., A.E.R.)
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Allan E. Rettie
Department of Medicinal Chemistry, University of Washington, Seattle, Washington (M.G.M., N.T.A., A.E.R.)
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Abstract

In this study, IC50 shift and time-dependent inhibition (TDI) experiments were carried out to measure the ability of amiodarone (AMIO), and its circulating human metabolites, to reversibly and irreversibly inhibit CYP1A2, CYP2C9, CYP2D6, and CYP3A4 activities in human liver microsomes. The [I]u/Ki,u values were calculated and used to predict in vivo AMIO drug-drug interactions (DDIs) for pharmaceuticals metabolized by these four enzymes. Based on these values, the minor metabolite N,N-didesethylamiodarone (DDEA) is predicted to be the major cause of DDIs with xenobiotics primarily metabolized by CYP1A2, CYP2C9, or CYP3A4, while AMIO and its N-monodesethylamiodarone (MDEA) derivative are the most likely cause of interactions involving inhibition of CYP2D6 metabolism. AMIO drug interactions predicted from the reversible inhibition of the four P450 activities were found to be in good agreement with the magnitude of reported clinical DDIs with lidocaine, warfarin, metoprolol, and simvastatin. The TDI experiments showed DDEA to be a potent inactivator of CYP1A2 (KI = 0.46 μM, kinact = 0.030 minute−1), while MDEA was a moderate inactivator of both CYP2D6 (KI = 2.7 μM, kinact = 0.018 minute−1) and CYP3A4 (KI = 2.6 μM, kinact = 0.016 minute−1). For DDEA and MDEA, mechanism-based inactivation appears to occur through formation of a metabolic intermediate complex. Additional metabolic studies strongly suggest that CYP3A4 is the primary microsomal enzyme involved in the metabolism of AMIO to both MDEA and DDEA. In summary, these studies demonstrate both the diversity of inhibitory mechanisms with AMIO and the need to consider metabolites as the culprit in inhibitory P450-based DDIs.

Footnotes

    • Received May 21, 2015.
    • Accepted August 20, 2015.
  • This work was supported by the National Institutes of Health [Grant PO1 GM32165].

  • dx.doi.org/10.1124/dmd.115.065623.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (11)
Drug Metabolism and Disposition
Vol. 43, Issue 11
1 Nov 2015
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Research ArticleArticle

Inhibitory Metabolites in Amiodarone Drug-Drug Interactions

Matthew G. McDonald, Nicholas T. Au and Allan E. Rettie
Drug Metabolism and Disposition November 1, 2015, 43 (11) 1661-1669; DOI: https://doi.org/10.1124/dmd.115.065623

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Research ArticleArticle

Inhibitory Metabolites in Amiodarone Drug-Drug Interactions

Matthew G. McDonald, Nicholas T. Au and Allan E. Rettie
Drug Metabolism and Disposition November 1, 2015, 43 (11) 1661-1669; DOI: https://doi.org/10.1124/dmd.115.065623
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