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Identification of the metabolites of lesogaberan using linear trap quadrupole orbitrap mass spectrometry and hydrophilic interaction liquid chromatography.
MedLine Citation:
PMID:  23030741     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
1. In this study, hydrophilic interaction liquid chromatography (HILIC), radiochemical activity monitoring and linear trap quadrupole orbitrap mass spectrometry (MS) and tandem mass spectrometry (MS/MS) were used to identify the metabolites of a highly polar novel γ-aminobutyric acid type-B receptor agonist, lesogaberan, in rats. 2. Urine was collected from three male Wistar rats for 24 h after dosing with (14)C-labelled lesogaberan (170 mg/kg, 10 MBq/kg); plasma samples were taken 2 and 24 h after dosing. Pooled samples were separated by HILIC and eluents were analysed by radiochemical activity monitoring, MS and MS/MS. 3. Only the parent compound was detected in plasma, but six metabolites (M1-M6) were detected in urine. Analysis of MS and MS/MS data and comparison with synthetic reference standards enabled the identification of the structure of each metabolite. M1 was identified as the N-acetylated species [(2R)-3-acetamido-2-fluoropropyl]-phosphinic acid, and M6 as [(2R)-3-amino-2-fluoropropyl]-phosphonic acid. Metabolites M2 and M5 were the alcohol and carboxylic acid species 3-hydroxypropyl-phosphinic acid and 3-hydroxyphosphonoyl-propanoic acid, respectively, both of which had lost the fluorine atom present in the parent compound. M3 was the corresponding carboxylic acid species retaining the fluorine atom, (2R)-2-fluoro-3-hydroxyphosphonoyl-propanoic acid. Finally M4 was identified as [(2R)-2-fluoro-3-guanidino-propyl]-phosphinic acid.
Authors:
Anja Ekdahl; Ann Aurell-Holmberg; Neal Castagnoli
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-10-3
Journal Detail:
Title:  Xenobiotica; the fate of foreign compounds in biological systems     Volume:  -     ISSN:  1366-5928     ISO Abbreviation:  Xenobiotica     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-3     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  1306665     Medline TA:  Xenobiotica     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
AstraZeneca R&D , Mölndal , Sweden.
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