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First published on August 16, 2006; DOI: 10.1124/dmd.106.011692

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Received for publication June 29, 2006.
Revised August 7, 2006.
Accepted for publication August 14, 2006.

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 1*, Kengo Miyata 1, Koichi Omura 1, Takashi Iwanaga 1, Osamu Nagata 1

1 Fuji Yakuhin Co., Ltd.

* Address correspondence to: E-mail: l2-20640{at}fujiyakuhin.co.jp

Abstract

FYX-051, 4-(5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl)pyridine-2-carbonitrile, is a novel xanthine oxidoreductase (XOR) 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 oral 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, while 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.


Key words: glucuronidation, mass spectrometry, metabolite identification, phase II drug metabolism, structure elucidation


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Home page
 Drug Metab. Dispos.Home page
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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