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Metabolite identification of a new antitumor agent icotinib in rats using liquid chromatography/tandem mass spectrometry
Author(s) -
Guan Zhongmin,
Chen Xiaoyan,
Wang Yinxiang,
Zhong Dafang
Publication year - 2008
Publication title -
rapid communications in mass spectrometry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.528
H-Index - 136
eISSN - 1097-0231
pISSN - 0951-4198
DOI - 10.1002/rcm.3599
Subject(s) - chemistry , metabolite , mass spectrometry , chromatography , tandem mass spectrometry , liquid chromatography–mass spectrometry , metabolic pathway , hydroxylation , metabolism , biochemistry , enzyme
Icotinib, 4‐[(3‐ethynylphenyl)amino]‐6,7‐benzo‐12‐crown‐4‐quinazoline, is a new antitumor agent. The metabolic pathway of icotinib in rats was studied using liquid chromatography/tandem mass spectrometry (LC/MS n ) analysis. Full scan and selected ion monitoring modes were used to profile the possible metabolites of icotinib in rat urine, feces and bile samples. Four phase I metabolites (M1–M4) and two phase II metabolites (M5, M6) were detected and characterized. Multiple‐stage mass spectrometry and nuclear magnetic resonance (NMR) spectrometry were employed to elucidate structures of metabolites. Icotinib was metabolized to open the crown ether ring to form the main phase I metabolites. During metabolism, a reactive metabolite was formed. Using semicarbazide as a trapping agent, an intermediate arising from opening of the crown ether ring was detected as an aldehyde product by LC/MS/MS. These data indicated that ring opening of the crown ether was triggered by hydroxylation at the 8″‐position of the ring to form a hemiacetal intermediate, which was further oxidized or reduced. Finally, the metabolic pathway of icotinib in rats was proposed. Copyright © 2008 John Wiley & Sons, Ltd.