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Cytochrome P450-mediated bioactivation of the epidermal growth factor receptor inhibitor erlotinib to a reactive electrophile

Academic Article
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Overview

authors

  • Li, X. H.
  • Kamenecka, Theodore
  • Cameron, Michael

publication date

  • July 2010

journal

  • Drug Metabolism and Disposition  Journal

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.

subject areas

  • Animals
  • Biotransformation
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System
  • Dose-Response Relationship, Drug
  • Erlotinib Hydrochloride
  • Glutathione
  • Humans
  • In Vitro Techniques
  • Mice
  • Mice, Inbred C57BL
  • Microsomes
  • Quinazolines
  • Receptor, Epidermal Growth Factor
  • Time Factors
  • Tissue Distribution
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Identity

PubMed Central ID

  • PMC3202369

International Standard Serial Number (ISSN)

  • 0090-9556

Digital Object Identifier (DOI)

  • 10.1124/dmd.109.030361

PubMed ID

  • 20382753
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Additional Document Info

start page

  • 1238

end page

  • 1245

volume

  • 38

issue

  • 7

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