[Lani]

Drug Metab Dispos. 2011 Sep 30. [Epub ahead of print]
Human Metabolism of Lapatinib, a Dual Kinase Inhibitor: Implications for Hepatotoxicity.
Castellino S, O'Mara MJ, Koch KM, Borts D, Bowers GD, Maclauchlin C.
Source
1 GlaxoSmithKline;
Abstract
Lapatinib (Tykerb/Tyverb) is an important orally active dual tyrosine kinase inhibitor efficacious in combination therapy for patients with progressive HER2-overexpressing metastatic breast cancer. However, clinically significant liver injury has been reported which may be associated with lapatinib metabolic activation. We describe the metabolism and excretion of [(14)C]-lapatinib in six healthy human volunteers following a single oral dose of 250 mg and the potential relationships between metabolism and clinical hepatotoxicity. Overall, elimination showed high inter-subject variability, with fecal elimination being the predominant pathway representing a median of 92% of the dose with lapatinib as the largest component (ca. median 27% dose). In plasma, approximately 50% of the observed radioactivity was attributed to metabolites. Analysis of a 4 hour pooled plasma extract identified seven metabolites related by an N- and αcarbon oxidation cascade and oxidation. Fecal metabolites derived from three prominent pathways: N- and αcarbon oxidation, fluorobenzyl oxidative cleavage, and hydroxypyridine formation. Undoubtedly, several of the lapatinib metabolites can 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.

PMID: 21965624