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HILIC-UPLC-MS for Exploratory Urinary Metabolic Profiling in Toxicological Studies

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Biomolecular Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London SW7 2AZ, U.K., Department of Clinical Pharmacology, Drug Metabolism and Pharmacokinetics, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, U.K., Department of Chemistry and Laboratory of Forensic Medicine and Toxicology, Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54124 Greece, and Waters Corporation, 34 Maple Street, Milford, Massachusetts 01757, United States
* To whom correspondence should be addressed. E-mail: [email protected]
†Imperial College London.
∥Faculty of Medicine, Aristotle University of Thessaloniki.
§Department of Chemistry, Aristotle University of Thessaloniki.
⊥Waters Corporation.
Cite this: Anal. Chem. 2011, 83, 1, 382–390
Publication Date (Web):December 13, 2010
Copyright © 2010 American Chemical Society

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Hydrophilic interaction ultra performance liquid chromatography (HILIC-UPLC) permits the analysis of highly polar metabolites, providing complementary information to reversed-phase (RP) chromatography. HILIC-UPLC-TOF-MS was investigated for the global metabolic profiling of rat urine samples generated in an experimental hepatotoxicity study of galactosamine (galN) and the concomitant investigation of the protective effect of glycine. Within-run repeatability and stability over a large sample batch (>200 samples, 60 h run-time) was assessed through the repeat analysis of a quality control sample. Following system equilibration, excellent repeatability was observed in terms of retention time (CV < 1.7%), signal intensity (CV < 14%), and mass variability (<0.005 amu), providing a good measure of reproducibility. Classification of urinary metabolic profiles according to treatment was observed, with significant changes in specific metabolites after galN exposure, including increased urocanic acid, N-acetylglucosamine, and decreased 2-oxoglutarate. A novel finding from this HILIC-UPLC-MS approach was elevated urinary tyramine in galN-treated rats, reflecting disturbed amino acid metabolism. These results show HILIC-UPLC-MS to be a promising method for global metabolic profiling, demonstrating high within-run repeatability, even over an extended run time. Retention of polar endogenous analytes and xenobiotic metabolites was improved compared with RP studies, including galN, N-acetylglucosamine, oxoglutarate, and urocanic acid, enhancing metabolome coverage and potentially improving biomarker discovery.

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