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

Sijiang Liu; Zhaojin Yu

doi:10.1155/2021/8434204

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

J Anal Methods Chem. 2021 May 24:2021:8434204. doi: 10.1155/2021/8434204. eCollection 2021.

Authors

Sijiang Liu¹, Zhaojin Yu^{2

3}

Affiliations

¹ Department of Pharmaceutical Sciences, China Medical University-The Queen's University of Belfast Joint College, China Medical University, 77 Puhe Road, Shenyang 110122, China.
² Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, China.
³ Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors (China Medical University), Ministry of Education, China Medical University, Shenyang 110122, China.

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.