Novel sulphur-containing imatinib metabolites found by untargeted LC-HRMS analysis
Language English Country Netherlands Media print-electronic
Document type Journal Article
PubMed
28433749
DOI
10.1016/j.ejps.2017.04.014
PII: S0928-0987(17)30208-7
Knihovny.cz E-resources
- Keywords
- Compound Discoverer™, Glutathione, Imatinib, LC-HRMS, Metabolization, Untargeted metabolite profiling,
- MeSH
- Chromatography, Liquid MeSH
- Cysteine metabolism MeSH
- Cystine metabolism MeSH
- Imatinib Mesylate blood metabolism urine MeSH
- Protein Kinase Inhibitors blood metabolism urine MeSH
- Humans MeSH
- Antineoplastic Agents blood metabolism urine MeSH
- Sulfur blood metabolism urine MeSH
- Tandem Mass Spectrometry methods MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Cysteine MeSH
- Cystine MeSH
- Imatinib Mesylate MeSH
- Protein Kinase Inhibitors MeSH
- Antineoplastic Agents MeSH
- Sulfur MeSH
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.
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