Imatinib- <i>N</i> -oxide through chemical modification of imatinib and investigation of in-vitro potential toxic metabolite formation

Chemical modification of the tyrosine kinase inhibitor (TKI) imatinib was performed to obtain the imatinib-<i>N</i>-oxide, followed by metabolic profiling to study the possibilities of forming potential reactive metabolites of both imatinib and imatinib-<i>N</i>-oxide. The structure of the <i>N</i>-oxide metabolite was elucidated using various spectrometric techniques, including mass spectrometry, and nuclear magnetic resonance analysis. Metabolic profiling and the potential for reactive metabolite formation were investigated for both imatinib and the synthesized imatinib-<i>N</i>-oxide using rat liver microsomes and three chemical trapping agents (potassium cyanide, methoxylamine, and glutathione). Identification and characterization of the metabolites and any reactive metabolites were performed using an Agilent 6320 ion trap mass spectrometer. The results showed that imatinib-<i>N</i>-oxide produced two dihydroxy metabolites. Importantly, no reactive metabolites were observed for either imatinib or the imatinib-<i>N</i>-oxide in the presence of the chemical trapping agents. These findings contribute to the understanding of the metabolic fate and reactive metabolite potential of the TKI imatinib and its <i>N</i>-oxide metabolite, which is valuable information for assessing the safety and toxicological profile of this important oncology drug.