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Research ArticleArticle

Novel Metabolites of Amodiaquine Formed by CYP1A1 and CYP1B1: Structure Elucidation Using Electrochemistry, Mass Spectrometry, and NMR

Tove Johansson, Ulrik Jurva, Gunnar Grönberg, Lars Weidolf and Collen Masimirembwa
Drug Metabolism and Disposition March 2009, 37 (3) 571-579; DOI: https://doi.org/10.1124/dmd.108.025171
Tove Johansson
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Ulrik Jurva
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Gunnar Grönberg
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Lars Weidolf
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Collen Masimirembwa
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Abstract

An aldehyde metabolite of amodiaquine and desethylamodiaquine has been identified. The aldehyde was the major metabolite formed in incubations with two recombinantly expressed human cytochromes P450 (rP450s), namely, CYP1A1 and CYP1B1. The aldehyde metabolite was also formed, to a lesser extent, in both human and rat liver microsomes. When comparing results from incubations with liver microsomes from 3-methylcholanthrene-treated rats (inducing CYP1A1 and CYP1B1) with those from noninduced rats, a 6-fold increase of the aldehyde metabolite was observed in the rat liver microsomes after 3-methylcholanthrene treatment. The metabolic oxidation was mimicked by the electrochemical system, and the electrochemical oxidation product was matched with the metabolite from the in vitro incubations. The electrochemical generation of the aldehyde metabolite was repeated on a preparative scale, and the proposed structure was confirmed by NMR. Trapping of the aldehyde metabolite was done with methoxyl amine. Trapping experiments with N-acetyl cysteine revealed that the aldehyde was further oxidized to an aldehyde quinoneimine species, both in the rP450 incubations and in the electrochemical system. Three additional new metabolites of amodiaquine and desethylamodiaquine were formed via rCYP1A1 and rCYP1B1. Trace amounts of these metabolites were also observed in incubations with liver microsomes from 3-methylcholanthrene-treated rats. Tentative structures of the metabolites and adducts were assigned based on liquid chromatography/tandem mass spectrometry in combination with accurate mass measurements.

Footnotes

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

  • doi:10.1124/dmd.108.025171.

  • ABBREVIATIONS: rP450, recombinantly expressed cytochrome P450; HLM, human liver microsome; EC, electrochemistry; ESI/MS, electrospray ionization/mass spectrometry; P450, cytochrome P450; RLM, rat liver microsome; SPE, solid-phase extraction; NOE, nuclear Overhauser effect.

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

    • Received October 27, 2008.
    • Accepted December 12, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 37 (3)
Drug Metabolism and Disposition
Vol. 37, Issue 3
1 Mar 2009
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Research ArticleArticle

Novel Metabolites of Amodiaquine Formed by CYP1A1 and CYP1B1: Structure Elucidation Using Electrochemistry, Mass Spectrometry, and NMR

Tove Johansson, Ulrik Jurva, Gunnar Grönberg, Lars Weidolf and Collen Masimirembwa
Drug Metabolism and Disposition March 1, 2009, 37 (3) 571-579; DOI: https://doi.org/10.1124/dmd.108.025171

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Research ArticleArticle

Novel Metabolites of Amodiaquine Formed by CYP1A1 and CYP1B1: Structure Elucidation Using Electrochemistry, Mass Spectrometry, and NMR

Tove Johansson, Ulrik Jurva, Gunnar Grönberg, Lars Weidolf and Collen Masimirembwa
Drug Metabolism and Disposition March 1, 2009, 37 (3) 571-579; DOI: https://doi.org/10.1124/dmd.108.025171
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