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. 2021 May 24:2021:8434204.
doi: 10.1155/2021/8434204. eCollection 2021.

A Study of the Identification, Fragmentation Mode and Metabolic Pathways of Imatinib in Rats Using UHPLC-Q-TOF-MS/MS

Sijiang Liu  1 , Zhaojin Yu  2   3
Affiliations

A Study of the Identification, Fragmentation Mode and Metabolic Pathways of Imatinib in Rats Using UHPLC-Q-TOF-MS/MS

Sijiang Liu et al. J Anal Methods Chem. .

Abstract

In this study, The metabolites, metabolic pathways, and metabolic fragmentation mode of a tyrosine kinase inhibitor- (TKI-) imatinib in rats were investigated. The samples for analysis were pretreated via solid-phase extraction, and the metabolism of imatinib in rats was studied using ultra-high-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry (UHPLC-Q-TOF-MS/MS). Eighteen imatinib metabolites were identified in rat plasma, 21 in bile, 18 in urine, and 12 in feces. Twenty-seven of the above compounds were confirmed as metabolites of imatinib and 9 of them were newly discovered for the first time. Oxidation, hydroxylation, dealkylation, and catalytic dehydrogenation are the main metabolic pathways in phase I. For phase II, the main metabolic pathways were N-acetylation, methylation, cysteine, and glucuronidation binding. The fragment ions of imatinib and its metabolites were confirmed to be produced by the cleavage of the C-N bond at the amide bond. The newly discovered metabolite of imatinib was identified by UHPLC-Q-TOF-MS/MS. The metabolic pathway of imatinib and its fragmentation pattern were summarized. These results could be helpful to study the safety of imatinib for clinical use.

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Conflict of interest statement

The authors declare that there are no conflicts of interest regarding the publication of this paper.

Figures

Figure 1
Figure 1
The structure of imatinib.
Figure 2
Figure 2
In ESI positive ion mode, different energy collision spectra of [M + H]+ of IM and proposed fragmentation pattern of IM.
Figure 3
Figure 3
Base peak ion chromatograms of biological samples in positive ion mode. P0, B0, U0, and F0 represent blank samples of plasma, bile, urine, and feces from rats; P1, B1, U1, and F1 represent plasma, bile, urine, and feces samples from rats after oral administration of IM.
Figure 4
Figure 4
Extracted ion chromatograms (XIC) for metabolites in rats: (a) in blank plasma sample; (b) in plasma sample after an oral administration of IM.
Figure 5
Figure 5
UHPLC-Q-TOF-MS/MS of all metabolites.
Figure 6
Figure 6
Extracted ion chromatograms (XIC) for metabolites in rats: (a) in blank bile sample; (b) in bile sample after an oral administration of IM.
Figure 7
Figure 7
Extracted ion chromatograms (XIC) for metabolites in rats: (a) in blank urine sample; (b) in urine sample after an oral administration of IM.
Figure 8
Figure 8
Extracted ion chromatograms (XIC) for metabolites in rats: (a) in blank feces sample; (b) in feces sample after an oral administration of IM.
Figure 9
Figure 9
Proposed metabolic pathways of IM in rats.
See this image and copyright information in PMC

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