Abstract
The metabolism of 3-{[3-(2-Chlorophenyl)-4,5-dihydro-5-thioxo-1H-1,2,4-triazol-1-yl]methyl}benzonitrile (AR-C133611XX) was studied in isolated dog hepatocytes. The major metabolite of AR-C133611XX was characterized by high performance liquid chromatography-mass spectrometry and NMR and found to be the product of direct glucuronidation. Evidence from 1H and 13C-NMR chemical shifts and a long-range proton carbon correlation experiment was used to deduce that glucuronidation had taken place on the sulfur atom. Full NMR data on this unusual metabolite is presented. Substitution or replacement of the sulfur atom resulted in a significant decrease in the observed rate of glucuronidation.
Footnotes
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↵ 1 Current address: Organon Laboratories Ltd., Newhouse, Lanarkshire, ML1 5SH Scotland, UK.
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↵ 2 Current address: AstraZeneca R&D Alderley Park – Macclesfield, Alderley Park, Macclesfield, Cheshire, SK10 4TG UK.
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↵ 3 Abbreviations used are: AR-C133611XX, 3-{[3-(2-chlorophenyl)-4,5-dihydro-5-thioxo-1H-1,2,4-triazol-1-yl]methyl}benzonitrile; HPLC-MS, high performance liquid chromatography-mass spectrometry; DMEM, Dulbecco's modified Eagle's medium; BSA, bovine serum albumin; DMSO, dimethyl sulfoxide; amu, atomic mass unit(s); HSQC, heteronuclear single-quantum correlation; HMBC, heteronuclear multiple-bond correlation.
- Received January 13, 2003.
- Accepted March 11, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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