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

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 N-1- and N-2-glucuronidation and N-1- and N-2-glucosidation, respectively. N-1- and N-2-glucuronidation was observed in each species, whereas N-1- and N-2-glucosidation was mainly observed in dogs. With regard to the position of conjugation, N-1-conjugation was predominant; this resulted in a considerably higher amount of N-1-conjugate in each species than N-2-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.