A HILIC‐IM‐MS‐Based Pharmacometabodynamic Study of the Effects of Orally Administered Gefitinib on the Polar Urinary Metabolic Phenotypes of C57Bl6 Mice
Adam King, Lee A. Gethings, Robert S. Plumb, Ian D. Wilson
TL;DR
This study uses advanced analytical techniques to show how the drug gefitinib affects the urine metabolome of mice over 24 hours after oral administration.
Contribution
The study introduces a HILIC-IM-MS approach to reveal pharmacometabodynamic effects of gefitinib on polar urinary metabolites in mice.
Findings
Gefitinib caused time-dependent changes in polar urinary metabolites that correlated with drug concentrations.
Endogenous metabolites like 8-hydroxydeoxyguanosine and acetylcarnitine showed significant relative changes.
The effects suggest mechanism-based regulation of metabolic pathways by gefitinib.
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…
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Taxonomy
TopicsMetabolomics and Mass Spectrometry Studies · Analytical Chemistry and Chromatography · Pharmacogenetics and Drug Metabolism