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Drug Metabolism and Disposition Fast Forward
First published on August 30, 2007; DOI: 10.1124/dmd.107.017251

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Received for publication June 18, 2007.
Revised August 26, 2007.
Accepted for publication August 27, 2007.

Characterization of N-Glucuronidation of FYX-051-a New Xanthine Oxidoreductase Inhibitor

Koichi Omura 1*, Takashi Nakazawa 2, Takahiro Sato 2, Takashi Iwanaga 2, Osamu Nagata 2

1 Fuji Yakuhin Co.Ltd 2 Fuji Yakuhin Co., Ltd.

* Address correspondence to: E-mail: k-omura{at}fujiyakuhin.co.jp

Abstract

In humans, orally administered FYX-051—4-(5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl)pyridine-2-carbonitrile—is mainly excreted as triazole N1- and N2-glucuronides in urine. It is important to determine the enzyme(s) that catalyze the metabolism of a new drug in order to estimate individual differences and/or drug-drug interactions. Therefore, the characterization and mechanism of these glucuronidations were investigated using human liver microsomes (HLMs), human intestinal microsomes (HIMs), and recombinant human UDP-glucuronosyltransferase (UGT) isoforms to determine the UGT isoform(s) responsible for FYX-051 N1- and N2- glucuronidation. FYX-051 was metabolized to its N1- and N2-glucuronide forms by HLMs, and their Km values were 64.1 and 72.7 µM, respectively; however, FYX-051 was scarcely metabolized to its glucuronides by HIMs. Furthermore, among the recombinant human UGT isoforms, UGT1A1, UGT1A7, and UGT1A9 catalyzed the N1- and N2-glucuronidation of FYX-051. To estimate their contribution to FYX-051 glucuronidation, inhibition analysis with pooled HLMs was performed. Mefenamic acid—a UGT1A9 inhibitor—decreased FYX-051 N1- and N2-glucuronosyltransferase activities, whereas bilirubin—a UGT1A1 inhibitor—did not affect these activities. Furthermore, in the experiment using microsomes from 8 human livers, the N1- and N2-glucuronidation activity of FYX-051 was found to significantly correlate with the glucuronidation activity of propofol—a specific substrate of UGT1A9 (N1: r2 = 0.868, p < 0.01; N2: r2 = 0.775, p < 0.01). These results strongly suggested that the N1- and N2-glucuronidation of FYX-051 is mainly catalyzed by UGT1A9 in human livers.


Key words: glucuronidation, liver microsomes, phase II drug metabolism, UDP glucuronyltransferases


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Regio- and Stereospecific N-Glucuronidation of Medetomidine: The Differences between UDP Glucuronosyltransferase (UGT) 1A4 and UGT2B10 Account for the Complex Kinetics of Human Liver Microsomes
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