Structure elucidation of three isomeric metabolites of SYN-2836, a novel antifungal agent, in dogs via liquid chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry methodologies.
This paper presents liquid chromatography/mass spectrometry (LC/MS) and liquid chromatography/tandem mass spectrometry (LC/MS/MS) approaches for the rapid characterization of three urinary isomeric metabolites and their two precursor metabolites of SYN-2836, a novel antifungal agent, in dogs administered multiple oral doses of the agent (30 mg kg(-1) day(-1)). A collection of correlative data regarding the SYN-2836 metabolites was obtained by LC/MS and LC/MS/MS performed under complementary conditions such as the columns (C(18) vs cyano type), the mobile phase systems (acetonitrile-water-formic acid vs acetonitrile-water-ammonium acetate) and the electrospray ionization modes (positive vs negative). Metabolite identification was accomplished based on not only the LC/MS/MS data (product ion spectra) but also the LC/MS data indicating chromatographic behaviors of the metabolites. SYN-2836 and SYN-2869, an analog of the former, showed almost the same metabolic pathways following the same multiple-dose administration of the individual agents to the dogs. Therefore, correlation analysis in product ion spectra between corresponding metabolites of SYN-2836 and SYN-2869, and also in metabolic pathways between the two agents, was strategically used to facilitate the identification of the SYN-2836 (and SYN-2869 if necessary) metabolites. For the reason that various elucidation strategies were used complementarily, the chemical structures of the metabolites were unambiguously attained and the isomeric metabolites were explicitly differentiated without the use of other analytical methods. The methodologies used in this study may be applicable to metabolite screening of several structurally related agents simultaneously, promoting lead finding and optimization of drug candidates using a metabolism-based approach.
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Department of Biopharmaceutics and Pharmacokinetics, Naeja Pharmaceuticals Inc., 4290-91A Street, Edmonton, AB, T6E 5V2, Canada.
Poglod
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Micetich
R G
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Khan
J K
JK
D000818:Animals; D000935:Antifungal Agents / Q000032:analysis / Q000737:chemistry / Q000493:pharmacokinetics*; D001555:Benzene Derivatives / Q000737:chemistry / Q000652:urine; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004285:Dogs; D007536:Isomerism; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D015394:Molecular Structure; D010879:Piperazines / Q000032:analysis / Q000737:chemistry / Q000493:pharmacokinetics*; D014230:Triazoles / Q000032:analysis / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine
D000935:Antifungal Agents; D001555:Benzene Derivatives; D010879:Piperazines; C118964:Syn 2869; D014230:Triazoles