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Research ArticleArticle

Cytochrome P450-Mediated Bioactivation of the Epidermal Growth Factor Receptor Inhibitor Erlotinib to a Reactive Electrophile

Xiaohai Li, Theodore M. Kamenecka and Michael D. Cameron
Drug Metabolism and Disposition July 2010, 38 (7) 1238-1245; DOI: https://doi.org/10.1124/dmd.109.030361
Xiaohai Li
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Theodore M. Kamenecka
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Michael D. Cameron
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Abstract

The epidermal growth factor receptor tyrosine kinase inhibitor erlotinib (ERL) is approved for treatment of non–small-cell lung cancer. Numerous reports of ERL-associated toxicities are consistent with immune-mediated toxicity, including drug-induced hepatitis, interstitial lung disease, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Although the mechanism of toxicity has not been established, we present evidence that reactive intermediates are formed during the metabolism of ERL, which can covalently conjugate to the cysteine group of the peptide-mimetic GSH. Seven ERL-GSH conjugates were identified in incubations with hepatic microsomes. Cytochrome P450 (P450)-dependent adducts are proposed to be formed via reactive epoxide and electrophilic quinone-imine intermediates. In incubations of human liver microsomes, intestinal microsomes, pulmonary microsomes, and recombinant P450s, CYP3A4 was the primary enzyme responsible for the bioactivation of ERL; however, CYP1A1, CYP1A2, CYP3A5, and CYP2D6 were capable of catalyzing the bioactivation as well. During the metabolism of ERL, CYP3A4 and CYP3A5 are irreversibly inactivated by ERL in a time- and concentration-dependent manner. Inactivation was not dependent on oxidation of the ERL alkyne group to form a reactive oxirene or ketene, as shown by synthesizing analogs where the alkyne was replaced with a cyano group. CYP1A1, CYP1A2, and CYP2D6 were not inactivated despite catalyzing the formation of ERL-GSH adducts.

Footnotes

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

    doi:10.1124/dmd.109.030361.

  • ABBREVIATIONS:

    ERL
    erlotinib
    EGFR
    epidermal growth factor receptor
    P450
    cytochrome P450
    HLM
    human liver microsome
    DMSO
    dimethyl sulfoxide
    HPLC
    high-performance liquid chromatography
    MRM
    multiple reaction monitoring.

  • Received September 28, 2009.
  • Accepted April 9, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (7)
Drug Metabolism and Disposition
Vol. 38, Issue 7
1 Jul 2010
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Research ArticleArticle

Cytochrome P450-Mediated Bioactivation of the Epidermal Growth Factor Receptor Inhibitor Erlotinib to a Reactive Electrophile

Xiaohai Li, Theodore M. Kamenecka and Michael D. Cameron
Drug Metabolism and Disposition July 1, 2010, 38 (7) 1238-1245; DOI: https://doi.org/10.1124/dmd.109.030361

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Research ArticleArticle

Cytochrome P450-Mediated Bioactivation of the Epidermal Growth Factor Receptor Inhibitor Erlotinib to a Reactive Electrophile

Xiaohai Li, Theodore M. Kamenecka and Michael D. Cameron
Drug Metabolism and Disposition July 1, 2010, 38 (7) 1238-1245; DOI: https://doi.org/10.1124/dmd.109.030361
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