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Characterization of metabolites of a novel histamine H 2 ‐receptor antagonist, lafutidine, in human liver microsomes by liquid chromatography coupled with ion trap mass spectrometry
Author(s) -
Wang Yuya,
Chen Xiaoyan,
Li Qiang,
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.3558
Subject(s) - chemistry , mass spectrometry , chromatography , ion trap , electrospray ionization , fragmentation (computing) , atmospheric pressure chemical ionization , moiety , chemical ionization , ion , ionization , stereochemistry , organic chemistry , computer science , operating system
The metabolism of lafutidine in human liver microsomes was studied using liquid chromatography/ion trap mass spectrometry with electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI) sources. A total of 14 metabolites were identified including hydroxylated lafutidine and sulfonyl lafutidine as the major metabolites. The chemical properties and the MS n behaviors of lafutidine and all of its identified metabolites were studied in detail. Lafutidine had a fragmentation pattern as a result of homolytic bond cleavage in the MS/MS spectrum. This cleavage can form an odd‐electron ion with the loss of furan‐2‐ylmethyl radical (−81 Da with a proton shift), which then sequentially loses neutral groups in the MS 3 spectrum. This fragmentation sequence was also observed from the metabolites with the unchanged sulfinyl moiety. When the sulfinyl moiety was oxidized to the sulfonyl moiety, this fragmentation sequence did not exist, which could be used to identify S ‐oxidation metabolites of lafutidine. In general, N ‐oxides could produce distinct [M+H–O] + ions under LC/APCI‐MS due to the thermal activation in the desolvation region of the API source, which could be used to identify N ‐oxidation metabolites of lafutidine. In order to avoid the possibility of false positives, the MS/MS spectrum of the [M+H–O] + ion was compared with that of the non‐ N ‐oxidation metabolites or parent drug in the APCI source. If they were consistent, the structure could be finally confirmed. The exact masses for lafutidine and lafutidine N ‐oxide fragment ions were determined using an LTQ/Orbitrap mass spectrometer. Copyright © 2008 John Wiley & Sons, Ltd.