title: N-O glucuronidation: a major human metabolic pathway in the elimination of two novel anti-convulsant drug candidates.
abstract: 1. The urinary metabolites of the anti-convulsant compound 4-amino-1-(2,6-difluorobenzyl)-1H-1,2,3-triazolo[4,5-c]-pyridine hydrochloride (GI265080) obtained following a single oral dose to man have been detected and quantified relative to each other using 19F-NMR spectroscopy. 2. The human urinary metabolites of GI265080 were isolated using semipreparative HPLC and unequivocally characterized using 1H-NMR spectroscopy, two-dimensional heteronuclear NMR spectroscopy and mass spectrometry. The assignments of the N-(5)-oxide and the N-(5)-O-glucuronide metabolites of GI265080 were further confirmed by independent synthesis. The urinary metabolites obtained following single oral doses to dog and rat have also been isolated and characterized. 3. The human urinary metabolites of GI265080 comprise the N-(5)-oxide, the quaternary N+-(5)-glucuronide, the 7-hydroxy glucuronide and a glucuronide conjugate of the N-(5)-oxide. The N-(5)-O-glucuronide conjugate is a novel species in human metabolism and is a significant route of elimination of GI265080 in man. 4. The urinary metabolites of the potential anti-convulsant GW273293 (6-amino-3-(2,3,5-trichlorophenyl)pyrazin-2-ylamine) obtained following a single oral dose to man have also been isolated and characterized. The formation of a novel N-O-glucuronide was also observed and was shown to constitute a significant route of elimination of GW273293 in man.
authors.affiliation: Structural Identification Group, GlaxoSmithKline Research and Development, Ware, UK. imi2682@glaxowellcome.co.uk
authors.forename: I M
authors.initials: IM
authors.lastname: Ismail
authors.forename: G J
authors.initials: GJ
authors.lastname: Dear
authors.forename: A D
authors.initials: AD
authors.lastname: Roberts
authors.forename: R S
authors.initials: RS
authors.lastname: Plumb
authors.forename: J
authors.initials: J
authors.lastname: Ayrtont
authors.forename: B C
authors.initials: BC
authors.lastname: Sweatman
authors.forename: G D
authors.initials: GD
authors.lastname: Bowers
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry* / Q000378:metabolism* / Q000652:urine; D004285:Dogs; D005260:Female; D005461:Fluorine; D005464:Fluorobenzenes / Q000737:chemistry* / Q000378:metabolism* / Q000652:urine; D020719:Glucuronides / Q000737:chemistry / Q000378:metabolism / Q000652:urine; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D015394:Molecular Structure; D011719:Pyrazines / Q000737:chemistry* / Q000378:metabolism* / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000927:Anticonvulsants; D005464:Fluorobenzenes; C119734:GI 265080; C461059:GW273293; D020719:Glucuronides; D011719:Pyrazines; D005461:Fluorine