Abstract

Lapatinib (Tykerb, Tyverb) is an important orally active dual tyrosine kinase inhibitor efficacious in combination therapy for patients with progressive human epidermal receptor 2-overexpressing metastatic breast cancer. However, clinically significant liver injury, which may be associated with lapatinib metabolic activation, has been reported. We describe the metabolism and excretion of [¹⁴C]lapatinib in six healthy human volunteers after a single oral dose of 250 mg and the potential relationships between metabolism and clinical hepatotoxicity. Overall, elimination showed high intersubject variability, with fecal elimination being the predominant pathway, representing a median of 92% of the dose with lapatinib as the largest component (approximate median 27% of the dose). In plasma, approximately 50% of the observed radioactivity was attributed to metabolites. Analysis of a 4-h pooled plasma extract identified seven metabolites related by an N- and α-carbon oxidation cascade. Fecal metabolites derived from three prominent pathways: N- and α-carbon oxidation, fluorobenzyl oxidative cleavage, and hydroxypyridine formation. Several of the lapatinib metabolites can undoubtedly be linked to reactive species such as aldehydes or quinone imines. In addition to the contribution of these potentially reactive metabolites as suspects in clinical liver injury, the role of other disposition factors, including interaction with drug transporters, pharmacogenetics, or magnitude of the therapeutic dose, should not be discounted.