title: Metabolic profile of FYX-051 (4-(5-pyridin-4-yl-1h-[1,2,4]triazol-3-yl)pyridine-2-carbonitrile) in the rat, dog, monkey, and human: identification of N-glucuronides and N-glucosides.
abstract: FYX-051, 4-(5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl)pyridine-2-carbonitrile, is a novel xanthine oxidoreductase inhibitor that can be used for the treatment of gout and hyperuricemia. We examined the metabolism of FYX-051 in rats, dogs, monkeys, and human volunteers after the p.o. administration of this inhibitor. The main metabolites in urine were pyridine N-oxide in rats, triazole N-glucoside in dogs, and triazole N-glucuronide in monkeys and humans, respectively. Furthermore, N-glucuronidation and N-glucosidation were characterized by two types of conjugation: triazole N(1)- and N(2)-glucuronidation and N(1)- and N(2)-glucosidation, respectively. N(1)- and N(2)-glucuronidation was observed in each species, whereas N(1)- and N(2)-glucosidation was mainly observed in dogs. With regard to the position of conjugation, N(1)-conjugation was predominant; this resulted in a considerably higher amount of N(1)-conjugate in each species than N(2)-conjugate. The present results indicate that the conjugation reaction observed in FYX-051 metabolism is unique, i.e., N-glucuronidation and N-glucosidation occur at the same position of the triazole ring, resulting in the generation of four different conjugates in mammals. In addition, a urinary profile of FYX-051 metabolites in monkeys and humans was relatively similar; triazole N-glucuronides were mainly excreted in urine.
authors.affiliation: Research Laboratories 2, Fuji Yakuhin Co Ltd, 636-1 Iidashinden, Saitama, Japan. l2-20640@fujiyakuhin.co.jp
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakazawa
authors.forename: Kengo
authors.initials: K
authors.lastname: Miyata
authors.forename: Koichi
authors.initials: K
authors.lastname: Omura
authors.forename: Takashi
authors.initials: T
authors.lastname: Iwanaga
authors.forename: Osamu
authors.initials: O
authors.lastname: Nagata
mesh_terms: D000818:Animals; D004285:Dogs; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics / Q000652:urine; D005960:Glucosides / Q000652:urine*; D020719:Glucuronides / Q000652:urine*; D006801:Humans; D008252:Macaca fascicularis; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D015394:Molecular Structure; D009570:Nitriles / Q000378:metabolism / Q000493:pharmacokinetics / Q000652:urine; D011725:Pyridines / Q000378:metabolism / Q000493:pharmacokinetics / Q000652:urine; D051381:Rats; D011919:Rats, Inbred Strains; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D005960:Glucosides; D020719:Glucuronides; D009570:Nitriles; D011725:Pyridines; C504882:FYX-051; D014969:Xanthine Oxidase