Defining the Relationship between the Bioactivation of Lapatinib by CYP3A and Lapatinib-Induced Hepatotoxicity
Year: 2014
Type: dissertation
Abstract: Lapatinib was the first orally active dual tyrosine kinase inhibitor (TKI) of the epidermal growth factor receptor (EGFR, ErbB1) and human epidermal receptor 2 (HER2, ErbB2) to be approved by the US Food and Drug Administration (FDA).In 2008, the FDA issued a black-box warning for lapatinib idiosyncratic hepatotoxicity, which was observed in a small proportion of patients (<1%) in clinical trials and during post-market surveillance.In combination with other factors, metabolic activation has been suggested to play an important role in lapatinib hepatotoxicity.Lapatinib is metabolized by both cytochrome P450 3A4 and 3A5 to yield an O-debenzylated metabolite (LAP-OH), which can be further oxidized to a reactive quinoneimine that is captured by glutathione.The effect of pharmacogenetic polymorphisms of CYP3A5 on lapatinib metabolism in human liver microsomes was investigated and it was determined that a high-activity CYP3A5 genotype resulted in increased formation of the reactive metabolite glutathione conjugate in vitro.This suggests that genetic polymorphisms of CYP3A5 could affect the pharmacokinetics of lapatinib and impact the incidence of hepatotoxicity in Chapter 3: Metabolism and Cytotoxicity of Lapatinib and its Debenzylated Metabolite in Hepatocyte Cell Lines ......................
Author: Michelle D. Wahlin
Language: English
Subfield: Pharmacology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2386789781