A HILIC-IM-MS-Based Pharmacometabodynamic Study of the Effects of Orally Administered Gefitinib on the Polar Urinary Metabolic Phenotypes of C57Bl6 Mice

Abstract

The effects of the anilinoquinazoline tyrosine kinase inhibitor (TKI) gefitinib on the polar urinary metabolome of mice following oral administration (50 mg/kg) were studied over the 24 h period post dose. Analysis was performed using a hydrophilic interaction liquid chromatographic separation (HILIC) hyphenated to cyclic ion mobility (cIM) and mass spectrometry (MS). This investigation revealed numerous time-dependent changes in the polar urinary metabolic phenotype of gefitinib-dosed mice that mirrored the plasma concentrations and urinary excretion of the drug and its metabolites. These changes showed both relative increases and decreases in the amounts of various endogenous metabolites, including 8-hydroxydeoxyguanosine, thymidine, acetylcarnitine, isobutyrylcarnitine, myristoylglycine, 3-phenylpropionylglycine, cyclic AMP, 19-oxotestosterone, and 3′-asparagine-AMP. These changes were generally seen to be greatest at the time of the highest plasma and urinary concentrations of gefitinib. The concordance of these effects on the urinary metabolome with plasma/urine drug concentrations strongly implies a range of pharmacometabodynamic effects pointing to mechanism-based regulation of a number of endogenous metabolic pathways by gefitinib.