RT Journal Article
SR Electronic
T1 Metabolic Profile of FYX-051 (4-(5-Pyridin-4-yl-1<em>H</em>-[1,2,4]triazol-3-yl)pyridine-2-carbonitrile) in the Rat, Dog, Monkey, and Human: Identification of <em>N</em>-Glucuronides and <em>N</em>-Glucosides
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1880
OP 1886
DO 10.1124/dmd.106.011692
VO 34
IS 11
A1 Takashi Nakazawa
A1 Kengo Miyata
A1 Koichi Omura
A1 Takashi Iwanaga
A1 Osamu Nagata
YR 2006
UL http://dmd.aspetjournals.org/content/34/11/1880.abstract
AB 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 N1- and N2-glucuronidation and N1- and N2-glucosidation, respectively. N1- and N2-glucuronidation was observed in each species, whereas N1- and N2-glucosidation was mainly observed in dogs. With regard to the position of conjugation, N1-conjugation was predominant; this resulted in a considerably higher amount of N1-conjugate in each species than N2-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. The American Society for Pharmacology and Experimental Therapeutics