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

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 STATEMENTThis 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.

Roles of selected non-P450 human oxidoreductase enzymes in protective and toxic effects of chemicals: review and compilation of reactions

“…Oxycodone is extensively metabolized by P450 enzymes, but it is also converted to oxycodone N -oxide by FMO3 (Cashman et al 2020 ). The N -oxide metabolite was found to be retro-reduced back to oxycodone by AOX, quinone reductase, and hemoglobin (Table 15 ) (Fig.…”

“…30 ), an important signaling molecule involved in numerous physiological functions, including vasodilation, platelet aggregation, and immune response (Godber et al 2000 ; Li et al 2009 ; Maia et al 2015 ). AOX is also known to reduce a variety of other functional groups, including N - and S -oxides, heterocycles, and nitro groups (Amano et al 2018 ; Cashman et al 2020 ; Dalvie and Di 2019 ; Ogiso et al 2018 ; Pryde et al 2010 ; Sung et al 2020 ).

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Non-P450 Drug-Metabolizing Enzymes: Contribution to Drug Disposition, Toxicity, and Development

“…Representative substrates of FMO3 include cimetidine, ranitidine, and a sulfide metabolite of sulindac. FMO3 catalyzes the S-and N-oxygenation of cimetidine and ranitidine, both H 2 -receptor antagonists, respectively, to pharmacologically inactivate metabolites (10,11). Sulindac is converted to a pharmacologically active sulfide form via a reduction reaction (12), and the sulfide form is S-oxygenated by FMO3 to sulindac (13); thus, FMO3 contributes to the pharmacological inactivation of sulindac.…”