topiroxostat and purine

To clarify the toxicological aspects of FYX-051, a xanthine oxidoreductase inhibitor, which is currently being developed as a therapeutic agent against gout and hyperuricemia, we performed the study focused on species differences in FYX-051-induced nephropathy. In the repeated toxicology testing by oral administration, nephropathy was seen at 1 mg/kg and more in rats and at 100 mg/kg in dogs, in contrast to no toxicity even at the practical maximum dose (300 mg/kg) in monkeys. The HPLC and LC-MS/MS analyses of intrarenal deposits in dogs have proven that the entity was xanthine. The study on dose dependency of pharmacokinetics, pharmacodynamics, urinary xanthine excretion, and kidney xanthine content by oral administration at 0.3, 1, and 3 mg/kg to rats revealed the involvement of xanthine in the occurrence of nephropathy, thus suggesting that plasma concentrations of FYX-051 can contribute to species differences. Regarding the possible factors of species differences, the daily urinary excretion of total purine metabolites was 30.5- and 6.3-fold greater in rats and dogs, respectively, than in monkeys. Urinary xanthine solubility was 2.3- and 6.3-fold higher in dogs and monkeys, respectively, than in rats. Plasma concentrations of FYX-051 were fivefold higher in rats than in dogs and monkeys, without differences between the latter two species. Therefore, the present study indicated that species differences in nephropathy were produced by the combined effects of purine metabolism, urinary xanthine solubility, and plasma concentrations of FYX-051.

Topics: Administration, Oral; Animals; Dogs; Dose-Response Relationship, Drug; Enzyme Inhibitors; Kidney Diseases; Macaca fascicularis; Male; Nitriles; Purines; Pyridines; Rats; Rats, Sprague-Dawley; Solubility; Species Specificity; Toxicity Tests; Xanthine; Xanthine Dehydrogenase