Exploring the Mechanism of CYP3A4 Inactivation by Lapatinib Through In Vitro Metabolite Char.

Exploring the Mechanism of CYP3A4 Inactivation by Lapatinib Through In Vitro Metabolite Char.

Aired:  3/6/2013 10:00:00 AM

Metabolism-dependent inhibition of cytochrome P450 enzymes has the potential to cause clinically-relevant drug-drug interactions. Alkylamine drugs are known for their propensity to cause CYP inhibition by formation of a metabolite that binds quasi-irreversibly to the ferrous heme iron of the enzyme. The secondary alkylamine drug lapatinib has been linked both to drug-induced liver injury and quasi-irreversible inhibition of CYP3A4. In the present study, in vitro techniques to probe reversibility of enzyme inactivation were combined with metabolite profiling by high-resolution liquid chromatography with accurate mass spectrometry to explore the mechanism of CYP3A4 inactivation associated with lapatinib metabolism.

Key concepts discussed in this webinar will include:

  • Insight into metabolism-dependent CYP inhibition by alkylamines
  • Utility of in vitro reversibility assays
  • Mechanism of CYP3A4 inactivation by the tyrosine kinase inhibitor lapatinib

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