caa a22 4500 445853913 CHVBK 20180317145422.0 cr unu---uuuuu 170323e20110501xx s 000 0 eng 10.1007/s00204-010-0598-5 doi (NATIONALLICENCE)springer-10.1007/s00204-010-0598-5 Study on species differences in nephropathy induced by FYX-051, a xanthine oxidoreductase inhibitor [Elektronische Daten] [Takeo Shimo, Naoki Ashizawa, Mitsuyoshi Moto, Takashi Iwanaga, Osamu Nagata] 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 1mg/kg and more in rats and at 100mg/kg in dogs, in contrast to no toxicity even at the practical maximum dose (300mg/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 3mg/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. Springer-Verlag, 2010 FYX-051 nationallicence Xanthine oxidoreductase inhibitor nationallicence Nephropathy nationallicence Species differences nationallicence Shimo Takeo Research Laboratories 2, Fuji Yakuhin Co., Ltd., 636-1 Iidashinden, Nishi-ku, 331-0068, Saitama, Japan aut Ashizawa Naoki Research Laboratories 2, Fuji Yakuhin Co., Ltd., 636-1 Iidashinden, Nishi-ku, 331-0068, Saitama, Japan aut Moto Mitsuyoshi Research Laboratories 2, Fuji Yakuhin Co., Ltd., 636-1 Iidashinden, Nishi-ku, 331-0068, Saitama, Japan aut Iwanaga Takashi Research Laboratories 2, Fuji Yakuhin Co., Ltd., 636-1 Iidashinden, Nishi-ku, 331-0068, Saitama, Japan aut Nagata Osamu Research Laboratories 2, Fuji Yakuhin Co., Ltd., 636-1 Iidashinden, Nishi-ku, 331-0068, Saitama, Japan aut Archives of Toxicology Springer-Verlag 85/5(2011-05-01), 505-512 0340-5761 85:5<505 2011 85 204 https://doi.org/10.1007/s00204-010-0598-5 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00204-010-0598-5 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Shimo Takeo Research Laboratories 2, Fuji Yakuhin Co., Ltd., 636-1 Iidashinden, Nishi-ku, 331-0068, Saitama, Japan aut NATIONALLICENCE 700 1- Ashizawa Naoki Research Laboratories 2, Fuji Yakuhin Co., Ltd., 636-1 Iidashinden, Nishi-ku, 331-0068, Saitama, Japan aut NATIONALLICENCE 700 1- Moto Mitsuyoshi Research Laboratories 2, Fuji Yakuhin Co., Ltd., 636-1 Iidashinden, Nishi-ku, 331-0068, Saitama, Japan aut NATIONALLICENCE 700 1- Iwanaga Takashi Research Laboratories 2, Fuji Yakuhin Co., Ltd., 636-1 Iidashinden, Nishi-ku, 331-0068, Saitama, Japan aut NATIONALLICENCE 700 1- Nagata Osamu Research Laboratories 2, Fuji Yakuhin Co., Ltd., 636-1 Iidashinden, Nishi-ku, 331-0068, Saitama, Japan aut NATIONALLICENCE 773 0- Archives of Toxicology Springer-Verlag 85/5(2011-05-01), 505-512 0340-5761 85:5<505 2011 85 204 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer