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Drug Metabolism and Disposition Fast Forward
First published on August 16, 2006; DOI: 10.1124/dmd.106.011692

0090-9556/06/3411-1880-1886$20.00
DMD 34:1880-1886, 2006

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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

Takashi Nakazawa, Kengo Miyata, Koichi Omura, Takashi Iwanaga, and Osamu Nagata

Research Laboratories 2, Fuji Yakuhin Co., Ltd., Saitama, Japan

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.

Address correspondence to: Takashi Nakazawa, Research Laboratories 2, Fuji Yakuhin Co., Ltd., 636-1 Iidashinden, Nishi-ku, Saitama 331-0068, Japan. E-mail: l2-20640{at}fujiyakuhin.co.jp




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K. Omura, T. Nakazawa, T. Sato, T. Iwanaga, and O. Nagata
Characterization of N-Glucuronidation of 4-(5-Pyridin-4-yl-1H-[1,2,4]triazol-3-yl) pyridine-2-carbonitrile (FYX-051): A New Xanthine Oxidoreductase Inhibitor
Drug Metab. Dispos., December 1, 2007; 35(12): 2143 - 2148.
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