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.

中文翻译：

---

用UHPLC-Q-TOF-MS / MS研究伊马替尼在大鼠中的鉴定，片段化模式和代谢途径

在这项研究中，研究了大鼠酪氨酸激酶抑制剂-（TKI-）伊马替尼的代谢产物，代谢途径和代谢片段化模式。通过固相萃取对分析样品进行预处理，并使用超高效液相色谱-四极杆飞行时间质谱（UHPLC-Q-TOF-MS / MS）研究伊马替尼在大鼠中的代谢。在大鼠血浆中鉴定出18种伊马替尼代谢产物，在胆汁中鉴定出21种，在尿液中鉴定出18种，在粪便中鉴定出12种。上述化合物中有27种被确认为伊马替尼的代谢产物，其中9种是首次被新发现。氧化，羟基化，脱烷基和催化脱氢是I期的主要代谢途径。对于II期，主要的代谢途径是N-乙酰化，甲基化，半胱氨酸和葡萄糖醛酸化结合。确认伊马替尼及其代谢物的碎片离子是由酰胺键上的CN键断裂所产生的。通过UHPLC-Q-TOF-MS / MS鉴定了新发现的伊马替尼代谢物。总结了伊马替尼的代谢途径及其片段化模式。这些结果可能有助于研究伊马替尼在临床上的安全性。