Abstract
Dacomitinib (DCB) is a second generation irreversible tyrosine kinase inhibitor (TKI) that is claimed to overcome the disadvantages of the resistance developed by the first line epidermal growth factor receptor (EGFR) TKIs. In the current study, metabolites of phase I for DCB were systematically explored. DCB reactive metabolites were also investigated in rat liver microsomes in presence of potassium cyanide or methoxylamine that were employed as capturing agents for iminium reactive intermediates and aldehyde, respectively, to form stable complexes which can be detected by LC-MS/MS. As a result, four in vitro phase I metabolites were observed with major pathway of piperidine ring hydroxylation. Additionally, two potentially reactive intermediates, one aldehyde and one iminium ions were characterized. Two different pathways of bioactivation were ultimately proposed.
Highlights
Lung carcinoma is the principal cause of death among all cancer types
The used rats were attained from the experimental animal care center at college of Pharmacy, King Saud University (KSA)
DCB chromatographic peak appears at 33.5 min in product ion (PI) chromatogram (Fig. 1A)
Summary
Lung carcinoma is the principal cause of death among all cancer types. Non-small cell lung cancer (NSCLC) represents the most widespread (around 90%) of all lung cancer in patients.[1,2,3,4,5] During the past few years, the epidermal growth factor receptor (EGFR) signaling pathway as a therapeutic target in NSCLC has gained more recognition.[6]. First line EGFR TKIs (e.g. erlotinib and ge tinib) had a very good response against these active mutations at the beginning.[7,8] acquired resistance (around 60%) and toxicities that occurred in treatment[9,10] reduce their therapeutic efficacies.[11,12]
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