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.
Laboratory of Drug Metabolism and Pharmacokinetics, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang 110016, PR China.
Zhongmin
Z
Guan
Xiaoyan
X
Chen
Yinxiang
Y
Wang
Dafang
D
Zhong
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