FYX-051, a Xanthine Oxidoreductase Inhibitor, Induces Nephropathy in Rats, but not in Monkeys

• Published in: Toxicologic pathology 2009-06, Vol.37 (4), p.438-445
• Main Authors: Shimo, Takeo, Ashizawa, Naoki, Moto, Mitsuyoshi, Matsumoto, Koji, Iwanaga, Takashi, Nagata, Osamu
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Biological and medical sciences; Data Interpretation, Statistical; Dose-Response Relationship, Drug; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - toxicity; Female; Humans; Hydrogen-Ion Concentration; Kidney - pathology; Kidney Diseases - chemically induced; Kidney Diseases - pathology; Macaca fascicularis; Male; Medical sciences; Nitriles - administration & dosage; Nitriles - toxicity; Purines - metabolism; Purines - urine; Pyridines - administration & dosage; Pyridines - toxicity; Rats; Rats, Sprague-Dawley; Solubility; Species Specificity; Toxicity Tests, Chronic; Toxicology; Xanthine Dehydrogenase - antagonists & inhibitors
• ISSN: 0192-6233; 1533-1601
• DOI: 10.1177/0192623309332995

The present studies were performed to investigate the possible mechanism of marked species differences on nephropathy found in the long-term toxicity study of FYX-051, a xanthine oxidoreductase inhibitor. In the twenty-six-week dose toxicity study in the rat, in which FYX-051 was administered by oral gavage at 0.04, 0.2, and 1 mg/kg, xanthine-mediated nephropathy was seen only at 1 mg/kg, despite the presence of xanthine crystals in urine at 0.2 mg/kg and more; however, in the fifty-two-week dose toxicity study in the monkey, in which FYX-051 was administered by oral gavage at 30, 100, and 300 mg/kg, no toxicities were seen, even at 300 mg/kg. These outcomes showed there would be 1500-fold or more differences in the mode of intrarenal xanthine deposition between rats and monkeys. Thus we performed the mechanistic study, and the following outcomes were obtained. First, the amount of urinary purine metabolites was thirty-fold higher in rats than in monkeys. Second, urinary xanthine solubility was sixfold higher in monkeys than in rats. Third, exposure levels of FYX-051 were five-fold higher in rats than in monkeys. Therefore, the present study indicated that the combined effects of purine metabolism, urinary xanthine solubility, and toxicokinetics would contribute to species differences in nephropathy, that is, absence of xanthine-mediated nephropathy in monkeys even at the highest dose of FYX-051.