title: 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.
abstract: In humans, orally administered 4-(5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl) pyridine-2-carbonitrile (FYX-051) is excreted mainly as triazole N(1)- and N(2)-glucuronides in urine. It is important to determine the enzyme(s) that catalyze the metabolism of a new drug 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 N(1)- and N(2)-glucuronidation. FYX-051 was metabolized to its N(1)- and N(2)-glucuronide forms by HLMs, and their K(m) values were 64.1 and 72.7 microM, 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 N(1)- and N(2)-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 N(1)- and N(2)-glucuronosyltransferase activities, whereas bilirubin, a UGT1A1 inhibitor, did not affect these activities. Furthermore, in the experiment using microsomes from eight human livers, the N(1)- and N(2)-glucuronidation activity of FYX-051 was found to significantly correlate with the glucuronidation activity of propofol, a specific substrate of UGT1A9 (N(1): r(2) = 0.868, p < 0.01; N(2): r(2) = 0.775, p < 0.01). These results strongly suggested that the N(1)- and N(2)-glucuronidation of FYX-051 is catalyzed mainly by UGT1A9 in human livers.
authors.affiliation: Research Laboratories 2, Fuji Yakuhin Co Ltd, Saitama, Japan. k-omura@fujiyakuhin.co.jp
authors.forename: Koichi
authors.initials: K
authors.lastname: Omura
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakazawa
authors.forename: Takahiro
authors.initials: T
authors.lastname: Sato
authors.forename: Takashi
authors.initials: T
authors.lastname: Iwanaga
authors.forename: Osamu
authors.initials: O
authors.lastname: Nagata
mesh_terms: D000818:Animals; D016367:Baculoviridae; D001663:Bilirubin / Q000378:metabolism; D001711:Biotransformation; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D020719:Glucuronides / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007313:Insecta; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects / Q000201:enzymology; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D008528:Mefenamic Acid / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009570:Nitriles / Q000378:metabolism* / Q000494:pharmacology; D015742:Propofol / Q000378:metabolism; D011725:Pyridines / Q000378:metabolism* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism; D013379:Substrate Specificity; D000090264:UDP-Glucuronosyltransferase 1A9; D014968:Xanthine Dehydrogenase / Q000037:antagonists & inhibitors*; D000099148:UGT1A1 Enzyme
chemical_list: D001663:Bilirubin; D004791:Enzyme Inhibitors; D020719:Glucuronides; D014453:Glucuronosyltransferase; D007527:Isoenzymes; D008528:Mefenamic Acid; D009570:Nitriles; D015742:Propofol; D011725:Pyridines; D011994:Recombinant Proteins; D000090264:UDP-Glucuronosyltransferase 1A9; D014968:Xanthine Dehydrogenase; D000099148:UGT1A1 Enzyme; C000715591:UGT1A9 protein, human; C504882:FYX-051; C524630:UGT1A7 protein, human