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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 November 14, 2019, dmd.119.089300; DOI: https://doi.org/10.1124/dmd.119.089300
John R. Cashman
Human BioMolecular Research Institute;
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  • For correspondence: jcashman@hbri.org
Mark Gohdes
Covance labs;
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Annelies de Kater
Pain Therapeutics
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Grant Schoenhard
Pain Therapeutics
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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 and humans showed substantial amount of recovered oxycodone N-oxide. In vivo, noroxycodone was formed as a major 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 small animals and humans. A new metabolite was quantified as oxycodone N-oxide. Oxycodone N-oxide undergoes extensive retro-reduction to oxycodone. A number of biological systems contribute to oxycodone N-oxide retro-reduction. This example of a tertiary amine N-oxide retro-reduction should be of widespread interest to readers of the journal.

  • brain/CNS
  • flavin-containing monooxygenase/FMO
  • NAD(P)H-quinone oxidoreductase
  • reductases
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 47 (12)
Drug Metabolism and Disposition
Vol. 47, Issue 12
1 Dec 2019
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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 November 14, 2019, dmd.119.089300; DOI: https://doi.org/10.1124/dmd.119.089300

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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 November 14, 2019, dmd.119.089300; DOI: https://doi.org/10.1124/dmd.119.089300
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