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Eur J Pharm Sci. 2017 Jun 15;104:335-343. doi: 10.1016/j.ejps.2017.04.014. Epub 2017 Apr 20.

Novel sulphur-containing imatinib metabolites found by untargeted LC-HRMS analysis.

Author information

1
Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University Olomouc, Hněvotínská 5, 779 00 Olomouc, Czech Republic; Department of Clinical Biochemistry, University Hospital Olomouc, I. P. Pavlova 6, 775 20 Olomouc, Czech Republic.
2
Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University Olomouc, Hněvotínská 5, 779 00 Olomouc, Czech Republic; Laboratory for Inherited Metabolic Disorders, Faculty of Medicine and Dentistry, Palacký University Olomouc, I. P. Pavlova 6, 775 20 Olomouc, Czech Republic; Department of Clinical Biochemistry, University Hospital Olomouc, I. P. Pavlova 6, 775 20 Olomouc, Czech Republic. Electronic address: david.friedecky@upol.cz.
3
Department of Hemato-Oncology, Faculty of Medicine and Dentistry, Palacký University Olomouc, I. P. Pavlova 6, 775 20 Olomouc, Czech Republic.
4
Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University Olomouc, Hněvotínská 5, 779 00 Olomouc, Czech Republic; Laboratory for Inherited Metabolic Disorders, Faculty of Medicine and Dentistry, Palacký University Olomouc, I. P. Pavlova 6, 775 20 Olomouc, Czech Republic; Department of Clinical Biochemistry, University Hospital Olomouc, I. P. Pavlova 6, 775 20 Olomouc, Czech Republic.

Abstract

Untargeted metabolite profiling using high-resolution mass spectrometry coupled with liquid chromatography (LC-HRMS), followed by data analysis with the Compound Discoverer 2.0™ software, was used to study the metabolism of imatinib in humans with chronic myeloid leukemia. Plasma samples from control (drug-free) and patient (treated with imatinib) groups were analyzed in full-scan mode and the unknown ions occurring only in the patient group were then, as potential imatinib metabolites, subjected to multi-stage fragmentation in order to elucidate their structure. The application of an untargeted approach, as described in this study, enabled the detection of 24 novel structurally unexpected metabolites. Several sulphur-containing compounds, probably originating after the reaction of reactive intermediates of imatinib with endogenous glutathione, were found and annotated as cysteine and cystine adducts. In the proposed mechanism, the cysteine adducts were formed after the rearrangement of piperazine moiety to imidazoline. On the contrary, in vivo S-N exchange occurred in the case of the cystine adducts. In addition, N-O exchange was observed in the collision cell in the course of the fragmentation of the cystine adducts. The presence of sulphur in the cysteine and cystine conjugates was proved by means of ultra-high resolution measurements using Orbitrap Elite. The detection of metabolites derived from glutathione might improve knowledge about the disposition of imatinib towards bioactivation and help to improve understanding of the mechanism of its hepatotoxicity or nephrotoxicity in humans.

KEYWORDS:

Compound Discoverer™; Glutathione; Imatinib; LC-HRMS; Metabolization; Untargeted metabolite profiling

PMID:
28433749
DOI:
10.1016/j.ejps.2017.04.014
[Indexed for MEDLINE]

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