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

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 ( 4-(5-Pyridin-4-yl-1H-[1,2,4]triazol-3-yl)pyridine-2-carbonitrile (FYX-051) is a newly synthesized xanthine oxidoreductase inhibitor, and its target indications are gout and hyperuricemia. The metabolism of FYX-051 has been evaluated in rats, dogs, monkeys, and humans; its major metabolites in humans were identified as triazole N 1 -and N 2 -glucuronides, and they were excreted into urine at 43.3 and 16

Metabolism and Pharmacokinetics of Morinidazole in Humans: Identification of Diastereoisomeric Morpholine N+-Glucuronides Catalyzed by UDP Glucuronosyltransferase 1A9

“…The K m values of M8-1 and M8-2 formation by UGT1A9 were 3.3 and 3.0 mM, respectively, which were lower than those by HLMs (11.3 and 15.1 mM). Differences in the glucuronidation K m values between recombinant UGT1A9 and HLMs had been previously observed and were probably due to protein-protein interaction (Fujiwara et al, 2007;Omura et al, 2007).…”

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

“…Among the human UGTs, UGT1A4 was largely considered as the enzyme "specializing" in N-glucuronidation because it is capable of conjugating different types of amines: primary aromatic amines, secondary and tertiary aliphatic amines, and secondary and tertiary aromatic N-heterocycles (Green and Tephly, 1998;Kaivosaari et al, 2002;Zenser et al, 2002;Kuehl and Murphy, 2003;Rowland et al, 2006). Several other human UGTs, including 1A1, 1A3, 1A7, 1A9, and 2B7, were documented to catalyze different N-glucuronidation reactions (Green and Tephly, 1998;Kaivosaari et al, 2002;Zenser et al, 2002;Staines et al, 2004;Girard et al, 2005;Kaji and Kume, 2005;Borlak et al, 2006;Rowland et al, 2006;Omura et al, 2007). Nevertheless, for all the latter enzymes, N-glucuronidation seems to be a minor reaction, whereas for UGT1A4, it is probably the major type of activity.…”

Comprehensive metabolic study of IOX4 in equine urine and plasma using liquid chromatography/electrospray ionization Q Exactive high‐resolution mass spectrometer for the purpose of doping control

“…In negative ion mode, M5 was detected as [M + HCOO] − and this postulation was further evidenced by the appearance of [M + CH 3 COO] − at the same retention time of M5 after the replacement of the mobile phase from formic acid to acetic acid. The conjugation of N ‐glucoside was not unusual because competitive conjugations of N ‐glucuronides and N ‐glucosides have been previously reported in different species 34–36 . Product ion spectra for M5 at CE 20 eV and 60 eV were almost the same as those of M4 (data not shown).…”