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Mechanism-based inactivation of cytochrome P450 3A4 by lapatinib

Woon Chien Teng1, Jing Wen Oh, Lee Sun New

  • 1Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore.

Molecular Pharmacology
|July 14, 2010
PubMed

Insights

Lapatinib, used for breast cancer, can cause liver damage by inactivating CYP3A4. This occurs through a reactive metabolite that binds to CYP3A4, potentially explaining its toxicity.

Area of Science:

  • Pharmacology
  • Drug Metabolism
  • Toxicology

Background:

  • Lapatinib (Tykerb) is an oral tyrosine kinase inhibitor for metastatic breast cancer.
  • Clinical use of lapatinib has been linked to fatal hepatotoxicity.
  • The mechanism underlying lapatinib-induced liver injury remains unclear.

Purpose of the Study:

  • To investigate the potential inhibition of cytochrome P450 3A4 (CYP3A4) by lapatinib.
  • To elucidate the mechanism by which lapatinib may cause idiosyncratic hepatotoxicity.

Main Methods:

  • Enzyme kinetics assays to determine lapatinib's interaction with CYP3A4.
  • Spectral analysis (Soret, CO-difference spectroscopy) to detect metabolite-intermediate complexes.
  • Incubation with human liver microsomes and glutathione (GSH) to identify reactive metabolites.
  • Coincubation with ketoconazole, a known CYP3A4 inhibitor, to assess adduct formation.

Main Results:

  • Lapatinib demonstrated time-, concentration-, and NADPH-dependent inactivation of CYP3A4 (k(inact) = 0.0202 min(-1), K(i) = 1.709 μM).
  • Testosterone protected CYP3A4 from inactivation, while GSH did not affect inactivation rates.
  • Spectral analysis indicated lapatinib is a mechanism-based inactivator, likely forming a reactive metabolite-GSH adduct via its O-dealkylated metabolite.
  • Ketoconazole inhibited the formation of this adduct.

Conclusions:

  • Lapatinib is a mechanism-based inactivator of CYP3A4.
  • Toxicity is likely mediated by a reactive metabolite, possibly a quinoneimine, formed from lapatinib's O-dealkylated metabolite.
  • This metabolite covalently modifies CYP3A4, contributing to lapatinib-induced hepatotoxicity.

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