Metabolite identification of a new antitumor agent icotinib in rats using liquid chromatography/tandem mass spectrometry.
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.
Guan
Zhongmin
Z
Laboratory of Drug Metabolism and Pharmacokinetics, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang 110016, PR China.
Chen
Xiaoyan
X
Wang
Yinxiang
Y
Zhong
Dafang
D
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism*; D001646:Bile / Q000737:chemistry; D002853:Chromatography, Liquid / Q000379:methods*; D043844:Crown Ethers / Q000737:chemistry / Q000378:metabolism*; D005243:Feces / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D015394:Molecular Structure; D008970:Molecular Weight; D011799:Quinazolines / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012015:Reference Standards; D052616:Solid Phase Extraction; D053719:Tandem Mass Spectrometry / Q000379:methods*; D016482:Urinalysis
D000970:Antineoplastic Agents; D043844:Crown Ethers; D011799:Quinazolines; C531470:icotinib