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Published on: July 3, 2013
Study on species differences in nephropathy induced by FYX-051, a xanthine oxidoreductase inhibitor
Takeo Shimo1, Naoki Ashizawa, Mitsuyoshi Moto
1Research Laboratories 2, Fuji Yakuhin Co., Ltd., Iidashinden, Nishi-ku, Saitama, Japan. t-shimo@fujiyakuhin.co.jp
Abstract:
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.
Insights
Species differences in FYX-051-induced kidney toxicity were clarified. The study found that purine metabolism, xanthine solubility, and drug concentration significantly influence nephropathy development in different species.
Area of Science:
- Toxicology
- Pharmacology
- Nephrology
Background:
- FYX-051 is a xanthine oxidoreductase inhibitor developed for gout and hyperuricemia.
- Understanding species differences in toxicity is crucial for drug development.
Purpose of the Study:
- To investigate the toxicological aspects of FYX-051, focusing on species differences in induced nephropathy.
- To elucidate the mechanisms underlying FYX-051-induced nephropathy.
Main Methods:
- Repeated oral toxicology testing in rats, dogs, and monkeys.
- HPLC and LC-MS/MS analysis of intrarenal deposits.
- Dose-dependent pharmacokinetic and pharmacodynamic studies in rats.
- Analysis of purine metabolism, urinary xanthine excretion, and solubility.
Main Results:
- Nephropathy observed in rats (≥1 mg/kg) and dogs (100 mg/kg), but not in monkeys (up to 300 mg/kg).
- Intrarenal deposits in dogs identified as xanthine, implicating it in nephropathy.
- Species differences in nephropathy linked to combined effects of purine metabolism, xanthine solubility, and FYX-051 plasma concentrations.
Conclusions:
- FYX-051-induced nephropathy is influenced by species-specific purine metabolism and xanthine handling.
- Plasma concentrations of FYX-051 contribute to observed species differences in toxicity.
- These findings are critical for the safe development of FYX-051 as a therapeutic agent.
