Urinary antihypertensive drug metabolite screening using molecular networking coupled to high-resolution mass spectrometry fragmentation

Van Der Hooft, J. J.J. , Padmanabhan, S. , Burgess, K. E.V. and Barrett, M. P. (2016) Urinary antihypertensive drug metabolite screening using molecular networking coupled to high-resolution mass spectrometry fragmentation. Metabolomics, 12, 125. (doi: 10.1007/s11306-016-1064-z) (PMID:27471437) (PMCID:PMC4932139)

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Introduction Mass spectrometry is the current technique of choice in studying drug metabolism. High-resolution mass spectrometry in combination with MS/MS gas-phase experiments has the potential to contribute to rapid advances in this field. However, the data emerging from such fragmentation spectral files pose challenges to downstream analysis, given their complexity and size. Objectives This study aims to detect and visualize antihypertensive drug metabolites in untargeted metabolomics experiments based on the spectral similarity of their fragmentation spectra. Furthermore, spectral clusters of endogenous metabolites were also examined. Methods Here we apply a molecular networking approach to seek drugs and their metabolites, in fragmentation spectra from urine derived from a cohort of 26 patients on antihypertensive therapy. The mass spectrometry data was collected on a Thermo Q-Exactive coupled to pHILIC chromatography using data dependent analysis (DDA) MS/MS gas-phase experiments. Results In total, 165 separate drug metabolites were found and structurally annotated (17 by spectral matching and 122 by classification based on a clustered fragmentation pattern). The clusters could be traced to 13 drugs including the known antihypertensives verapamil, losartan and amlodipine. The molecular networking approach also generated clusters of endogenous metabolites, including carnitine derivatives, and conjugates containing glutamine, glutamate and trigonelline. Conclusions The approach offers unprecedented capability in the untargeted identification of drugs and their metabolites at the population level and has great potential to contribute to understanding stratified responses to drugs where differences in drug metabolism may determine treatment outcome.

Item Type:Articles
Additional Information:A correction to this article is available at http://dx.doi.org/10.1007/s11306-016-1078-6.
Glasgow Author(s) Enlighten ID:Van Der Hooft, Mr Justin and Burgess, Dr Karl and Padmanabhan, Professor Sandosh and Barrett, Professor Michael
Authors: Van Der Hooft, J. J.J., Padmanabhan, S., Burgess, K. E.V., and Barrett, M. P.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:Metabolomics
ISSN (Online):1573-3890
Published Online:05 July 2016
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in Metabolomics 12:125
Publisher Policy:Reproduced under a Creative Commons License
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
721851ISSF Year 4 - Pilot ProjectsAnna DominiczakWellcome Trust (WELLCOME)105614/Z/14/ZRI CARDIOVASCULAR & MEDICAL SCIENCES
371798The Wellcome Centre for Molecular Parasitology ( Core Support )Andrew WatersWellcome Trust (WELLCOME)085349/B/08/ZIII - PARASITOLOGY
690421Glasgow Molecular Pathology (GMP) NodeKarin OienMedical Research Council (MRC)MR/N005813/1ICS - EXPERIMENTAL THERAPEUTICS