ISSN:
1052-9306
Keywords:
Chemistry
;
Analytical Chemistry and Spectroscopy
Source:
Wiley InterScience Backfile Collection 1832-2000
Topics:
Chemistry and Pharmacology
Notes:
The metabolites of an anxiolytic drug candidate U-78875 {3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5-(1-methylethyl)-imidazo[1,5-α]quinoxalin-4(5H)-one; I} were investigated in female rat faecal extracts following a single oral dose of (14C)I. Initial metabolite profiling was performed by high-performance liquid chromatography incorporating homogeneous (i.e. liquid scintillant added post-column) radiochemical detection (radio-HPLC). This indicated the presence of parent drug and one minor metabolite. Because liquid scintillant is incompatible with thermospray interfaces, subsequent analysis by thermospray/HPLC/MS (TSP/LC/MS) incorporated radiochemical detection in heterogeneous (i.e. solid scintillant) mode and ultraviolet (UV) diode array detection. This revealed that the peak thought previously to be parent drug contained two components: a metabolite (major) and parent drug (minor). The UV spectrum and TSP/LC/MS/MS daughter ion analysis led to the proposition of a bisamide structure for the major metabolite. Chemical synthesis was used to confirm this structure. TSP/LC/MS indicated that the molecular weight of the minor metabolite was 16 u higher than the bisamide, suggesting an oxidized analogue. Attempts to obtain a daughter ion spectrum on this minor metabolite proved unsuccessful. On-line radiochemical and UV diode array detection greatly facilitates the TSP/LC/MS characterization of metabolites from studies using radiolabelled drugs.
Additional Material:
6 Ill.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1002/bms.1200230102
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