NMR identification of an S-linked glucuronide of a triazole thione formed in vitro.
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.
Martin
Iain J
IJ
Department of Physical and Metabolic Science, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, LE11 5RH, UK.
Lewis
Richard J
RJ
Bonnert
Roger V
RV
Cage
Peter
P
Moody
Graeme C
GC
D000818:Animals; D002250:Carbon Radioisotopes; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D020719:Glucuronides / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D009570:Nitriles / Q000378:metabolism*; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors; D013455:Sulfur / Q000378:metabolism; D014230:Triazoles / Q000378:metabolism*
C480278:AR-C133611XX; D002250:Carbon Radioisotopes; D020719:Glucuronides; D009570:Nitriles; D023063:Receptors, Interleukin-8B; D014230:Triazoles; D013455:Sulfur