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Research ArticleArticle

In Vitro Metabolism Studies of Nomifensine Monooxygenation Pathways: Metabolite Identification, Reaction Phenotyping, and Bioactivation Mechanism

Jian Yu, Dean G. Brown and Doug Burdette
Drug Metabolism and Disposition October 2010, 38 (10) 1767-1778; DOI: https://doi.org/10.1124/dmd.110.033910
Jian Yu
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Dean G. Brown
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Doug Burdette
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Abstract

Multiple GSH adducts of the oxidative products of nomifensine (M1–M9) in human hepatocytes and liver microsomes have been identified recently. The current study reports three new types of monooxygenated metabolites of nomifensine identified in human liver microsomes: C-linked hydroxylated metabolites with modifications at the A ring (H1 and H4), an N-hydroxylamine (H6), and nomifensine N-oxides (H7 and H8). GSH conjugate formation in incubates containing cDNA-expressed P450s and GSH suggests that nomifensine GSH-sulfinamides (M1 and M2) are formed through the reaction between GSH and the oxidative product of H6. C-linked GSH conjugates M3, M4, M5, and M6 are probably formed via nomifensine benzoquinone imine intermediates via H4 and/or nomifensine epoxides. C-linked GSH conjugates M7, M8, and M9 are probably formed through similar mechanisms via H1. Nomifensine N-oxides do not form reactive metabolites that react with GSH. In vitro metabolism studies using a panel of cDNA-expressed human P450 and flavin monooxygenase (FMO) isoforms (CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5, FMO1, FMO3, and FMO5) indicated that CYP3A4, CYP2C19, and CYP2B6 generate the largest quantities of H1, H4, and H6, respectively. H7 and H8 are formed almost exclusively by FMOs. The contribution of the individual P450s involved in the formation of H1, H4, and H6 in human liver microsomes was confirmed by the inhibition of product formation by monoclonal anti-cytochrome 450 antibodies. These results showed that CYP3A4 and CYP2B6 contributed primarily to the formation of H1 and H6, respectively. CYP2C19 and CYP1A2 seemed to contribute significantly to the formation of H4.

Footnotes

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

    doi:10.1124/dmd.110.033910.

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

  • ABBREVIATIONS:

    LC
    liquid chromatography
    MS/MS
    tandem mass spectrometry
    P450
    cytochrome P450
    FMO
    flavin monooxygenase
    UPLC
    ultraperformance liquid chromatography
    MS
    mass spectrometry
    CID
    collision-induced dissociation.

  • Received April 12, 2010.
  • Accepted July 1, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (10)
Drug Metabolism and Disposition
Vol. 38, Issue 10
1 Oct 2010
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Research ArticleArticle

In Vitro Metabolism Studies of Nomifensine Monooxygenation Pathways: Metabolite Identification, Reaction Phenotyping, and Bioactivation Mechanism

Jian Yu, Dean G. Brown and Doug Burdette
Drug Metabolism and Disposition October 1, 2010, 38 (10) 1767-1778; DOI: https://doi.org/10.1124/dmd.110.033910

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Research ArticleArticle

In Vitro Metabolism Studies of Nomifensine Monooxygenation Pathways: Metabolite Identification, Reaction Phenotyping, and Bioactivation Mechanism

Jian Yu, Dean G. Brown and Doug Burdette
Drug Metabolism and Disposition October 1, 2010, 38 (10) 1767-1778; DOI: https://doi.org/10.1124/dmd.110.033910
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