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Research ArticleArticle

Human Metabolism of Lapatinib, a Dual Kinase Inhibitor: Implications for Hepatotoxicity

Stephen Castellino, Michael O'Mara, Kevin Koch, David J. Borts, Gary D. Bowers and Christopher MacLauchlin
Drug Metabolism and Disposition January 2012, 40 (1) 139-150; DOI: https://doi.org/10.1124/dmd.111.040949
Stephen Castellino
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Michael O'Mara
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Kevin Koch
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David J. Borts
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Gary D. Bowers
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Christopher MacLauchlin
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Abstract

Lapatinib (Tykerb, Tyverb) is an important orally active dual tyrosine kinase inhibitor efficacious in combination therapy for patients with progressive human epidermal receptor 2-overexpressing metastatic breast cancer. However, clinically significant liver injury, which may be associated with lapatinib metabolic activation, has been reported. We describe the metabolism and excretion of [14C]lapatinib in six healthy human volunteers after a single oral dose of 250 mg and the potential relationships between metabolism and clinical hepatotoxicity. Overall, elimination showed high intersubject variability, with fecal elimination being the predominant pathway, representing a median of 92% of the dose with lapatinib as the largest component (approximate median 27% of the dose). In plasma, approximately 50% of the observed radioactivity was attributed to metabolites. Analysis of a 4-h pooled plasma extract identified seven metabolites related by an N- and α-carbon oxidation cascade. Fecal metabolites derived from three prominent pathways: N- and α-carbon oxidation, fluorobenzyl oxidative cleavage, and hydroxypyridine formation. Several of the lapatinib metabolites can undoubtedly be linked to reactive species such as aldehydes or quinone imines. In addition to the contribution of these potentially reactive metabolites as suspects in clinical liver injury, the role of other disposition factors, including interaction with drug transporters, pharmacogenetics, or magnitude of the therapeutic dose, should not be discounted.

Footnotes

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

    http://dx.doi.org/10.1124/dmd.111.040949.

  • ABBREVIATIONS:

    ErbB
    epidermal growth factor receptor
    HER2
    human epidermal growth factor receptor 2
    DILI
    drug-induced liver injury
    CP-724,714
    E-2-methoxy-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-acetamide
    ALT
    alanine aminotransferase
    HPLC
    high-performance liquid chromatography
    LC
    liquid chromatography
    MS/MS
    tandem mass spectrometry
    LSC
    liquid scintillation counting
    MS
    mass spectrometry
    BQL
    below the limit of quantification.

  • Received June 1, 2011.
  • Accepted September 30, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (1)
Drug Metabolism and Disposition
Vol. 40, Issue 1
1 Jan 2012
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Research ArticleArticle

HUMAN METABOLISM OF LAPATINIB: HEPATOTOXICITY IMPLICATIONS

Stephen Castellino, Michael O'Mara, Kevin Koch, David J. Borts, Gary D. Bowers and Christopher MacLauchlin
Drug Metabolism and Disposition January 1, 2012, 40 (1) 139-150; DOI: https://doi.org/10.1124/dmd.111.040949

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Research ArticleArticle

HUMAN METABOLISM OF LAPATINIB: HEPATOTOXICITY IMPLICATIONS

Stephen Castellino, Michael O'Mara, Kevin Koch, David J. Borts, Gary D. Bowers and Christopher MacLauchlin
Drug Metabolism and Disposition January 1, 2012, 40 (1) 139-150; DOI: https://doi.org/10.1124/dmd.111.040949
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