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Research ArticleArticle

The Oxidative Biotransformation of Losoxantrone (CI-941)

Ulf D. Renner, Georgios Piperopoulos, Rolf Gebhardt, Gerhard Ehninger and Klaus-Peter Zeller
Drug Metabolism and Disposition April 2002, 30 (4) 464-478; DOI: https://doi.org/10.1124/dmd.30.4.464
Ulf D. Renner
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Georgios Piperopoulos
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Rolf Gebhardt
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Gerhard Ehninger
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Klaus-Peter Zeller
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Abstract

The oxidative biotransformation of the anticancer drug 7-hydroxy-2-[2-[(2-hydroxyethyl)amino]ethyl]-5-[[2-[(2-hydroxyethyl)amino]ethyl]amino]anthra[1,9-cd]pyrazol-6(2H)-one dihydrochloride (losoxantrone, CI-941) after incubation of primary cultures of rat hepatocytes has been investigated. The structures of twelve losoxantrone metabolites have been elucidated by means of high-performance liquid chromatography-mass spectometry, tandem mass spectrometry, and two-dimensional NMR. In these mammalian hepatocytes, the CI-941 biotransformation includes a monohydroxylation of the phenolic substructure of the CI-941-chromophore via cytochrome P450 catalysis, resulting in metabolites having an ortho- andpara-hydroquinonoid substructure, respectively. The identification of a glutathione conjugate as a follow-up metabolite confirms the oxidative activation of theortho-hydroxylated losoxantrone metabolite. The oxidative activation establishes the ability of CI-941 to form covalent bonds to intracellular nucleophilic targets. Furthermore, the CI-941 metabolism was shown to be extremely suppressed in rat hepatocytes incubated with metyrapone. In contrast to these results, human tumor HepG2 cells did not show any CI-941 biotransformation after incubation.

Footnotes

  • Abbreviations used are::
    CI-941 or DuP-941
    7-hydroxy-2-[2-[(2-hydroxyethyl)amino]ethyl]-5-[[2-[(2-hydroxyethyl)ami-no]ethyl]amino]-anthra[1,9-cd]pyrazol-6(2H)-one dihydrochloride
    LC-MS
    liquid chromatography-mass spectrometry
    HPLC
    high-performance liquid chromatography
    TOCSY
    total correlation spectroscopy
    HMQC
    heteronuclear multiple-quantum coherence spectroscopy
    HMBC
    heteronuclear multiple-bond correlation spectroscopy
    VIS
    visible
    RIC
    reconstructed ion current
    CID
    collision-induced dissociation
    MS/MS
    tandem mass spectrometry
    CI-937
    teloxantrone
    • Received July 25, 2001.
    • Accepted January 14, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 30 (4)
Drug Metabolism and Disposition
Vol. 30, Issue 4
1 Apr 2002
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Research ArticleArticle

The Oxidative Biotransformation of Losoxantrone (CI-941)

Ulf D. Renner, Georgios Piperopoulos, Rolf Gebhardt, Gerhard Ehninger and Klaus-Peter Zeller
Drug Metabolism and Disposition April 1, 2002, 30 (4) 464-478; DOI: https://doi.org/10.1124/dmd.30.4.464

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Research ArticleArticle

The Oxidative Biotransformation of Losoxantrone (CI-941)

Ulf D. Renner, Georgios Piperopoulos, Rolf Gebhardt, Gerhard Ehninger and Klaus-Peter Zeller
Drug Metabolism and Disposition April 1, 2002, 30 (4) 464-478; DOI: https://doi.org/10.1124/dmd.30.4.464
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