In Vitro Inhibition of Human Aldehyde Oxidase Activity by Clinically Relevant Concentrations of Gefitinib and Erlotinib: Comparison with Select Metabolites, Molecular Docking Analysis, and Impact on Hepatic Metabolism of Zaleplon and Methotrexate.

Gefitinib and erlotinib are epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) with activity against metastatic non-small cell lung cancer. Aldehyde oxidase-1 (AOX1) is a cytosolic drug-metabolizing enzyme. We conducted an experimental and molecular docking study on the effect of gefitinib, erlotinib, and select metabolites on the in vitro catalytic activity of AOX1, as assessed by carbazeran 4-oxidation, and determined the impact of AOX1 inhibition on hepatic metabolism of zaleplon and methotrexate.