Defining the Relationship between the Bioactivation of Lapatinib by CYP3A and Lapatinib-Induced Hepatotoxicity
Wahlin, Michelle Diane
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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 vivo. HepaRG cells were established as a cellular model to study lapatinib hepatotoxicity. Pretreatment of cells with dexamethasone and rifampicin (CYP3A4 inducers) markedly enhanced the cytotoxicity of lapatinib and resulted in an increase in formation of LAP-OH, as well as glutathione and cysteine adducts of the reactive metabolite. A lapatinib analog deuterated at the site of oxidative debenzylation produced less debenzylated metabolite and glutathione conjugates than lapatinib itself. This decrease also corresponded to reduced lapatinib cytotoxicity in HepaRG cells. Finally, a CYP3A4 mutant with a single point mutation at position 108 (F108L) shifted the metabolic profile of lapatinib to one more similar to that of CYP3A5, thus demonstrating the importance of this CYP3A5 amino acid for the orientation of lapatinib in the enzyme active site. Taken together, these studies highlight the importance of metabolic activation of lapatinib by CYP3A4 and CYP3A5 to the hepatotoxicity of the drug. The use of analogs of lapatinib whose metabolism to LAP-OH is blocked by structural modification, or genotyping patients for expression levels of CYP3A5, may lead to a decrease in incidences of idiosyncratic hepatotoxicity with lapatinib treatment and should be further explored.
- Medicinal chemistry