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Research ArticleArticle

N-Oxygenation of Oxycodone and Retro-reduction of Oxycodone N-Oxide

John R. Cashman, Mark Gohdes, Annelies de Kater and Grant Schoenhard
Drug Metabolism and Disposition February 2020, 48 (2) 106-115; DOI: https://doi.org/10.1124/dmd.119.089300
John R. Cashman
Human BioMolecular Research Institute, San Diego, California (J.R.C.); Covance Laboratories, Inc., Madison, Wisconsin (M.G.); and Pain Therapeutics, Inc., Austin, Texas (A.K., G.S.)
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Mark Gohdes
Human BioMolecular Research Institute, San Diego, California (J.R.C.); Covance Laboratories, Inc., Madison, Wisconsin (M.G.); and Pain Therapeutics, Inc., Austin, Texas (A.K., G.S.)
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Annelies de Kater
Human BioMolecular Research Institute, San Diego, California (J.R.C.); Covance Laboratories, Inc., Madison, Wisconsin (M.G.); and Pain Therapeutics, Inc., Austin, Texas (A.K., G.S.)
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Grant Schoenhard
Human BioMolecular Research Institute, San Diego, California (J.R.C.); Covance Laboratories, Inc., Madison, Wisconsin (M.G.); and Pain Therapeutics, Inc., Austin, Texas (A.K., G.S.)
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Abstract

Oxycodone is used as a potent analgesic medication. Oxycodone is extensively metabolized. To fully describe its metabolism, the oxygenation of oxycodone to oxycodone N-oxide was investigated in hepatic preparations. The hypothesis tested was that oxycodone N-oxygenation was enzymatic and the amount of N-oxide detected was a consequence of both oxygenation and retro-reduction. Methods for testing the hypothesis included both in vitro and in vivo studies. Results indicated that oxycodone was N-oxygenated by the flavin-containing monooxygenase. Oxycodone N-oxide is chemically quite stable but in the presence of hepatic preparations and NADPH was retro-reduced to its parent compound oxycodone. Subsequently, oxycodone was metabolized to other metabolites including noroxycodone, noroxymorphone, and oxymorphone via cytochrome P-450. Retro-reduction of oxycodone N-oxide to oxycodone was facilitated by quinone reductase, aldehyde oxidase, and hemoglobin but not to a great extent by cytochrome P-450 or the flavin-containing monooxygenase. To confirm the in vitro observations, oxycodone was administered to rats and humans. In good agreement with in vitro results, substantial oxycodone N-oxide was observed in urine after oxycodone administration to rats and humans. Administration of oxycodone N-oxide to rats showed substantial amount of recovered oxycodone N-oxide. In vivo, noroxycodone was formed as a major rat urinary metabolite from oxycodone N-oxide presumably after retro-reduction to oxycodone and oxidative N-demethylation. To a lesser extent, oxycodone, noroxymorphone, and oxymorphone were observed as urinary metabolites.

SIGNIFICANCE STATEMENT This manuscript describes the N-oxygenation of oxycodone in vitro as well as in small animals and humans. A new metabolite was quantified as oxycodone N-oxide. Oxycodone N-oxide undergoes extensive retro-reduction to oxycodone. This re-establishes the metabolic profile of oxycodone and introduces new concepts about a metabolic futile cycle related to oxycodone metabolism.

Footnotes

    • Received September 12, 2019.
    • Accepted November 4, 2019.
  • Financial support for this work was provided by Pain Therapeutics, Inc.

  • https://doi.org/10.1124/dmd.119.089300.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 48 (2)
Drug Metabolism and Disposition
Vol. 48, Issue 2
1 Feb 2020
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Research ArticleArticle

Oxycodone N-Oxygenation, Oxycodone N-Oxide Retro-reduction

John R. Cashman, Mark Gohdes, Annelies de Kater and Grant Schoenhard
Drug Metabolism and Disposition February 1, 2020, 48 (2) 106-115; DOI: https://doi.org/10.1124/dmd.119.089300

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Research ArticleArticle

Oxycodone N-Oxygenation, Oxycodone N-Oxide Retro-reduction

John R. Cashman, Mark Gohdes, Annelies de Kater and Grant Schoenhard
Drug Metabolism and Disposition February 1, 2020, 48 (2) 106-115; DOI: https://doi.org/10.1124/dmd.119.089300
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