title: Study on toxicological aspects of crystal-mediated nephrotoxicity induced by FYX-051, a xanthine oxidoreductase inhibitor, in rats.
abstract: To clarify the toxicological aspects of crystal-mediated nephrotoxicity, we performed analysis concerning the correlation between representative kidney-related parameters and renal histopathology, using the individual data obtained from the 4-week toxicity studies of FYX-051, a xanthine oxidoreductase inhibitor, by oral administration at 1 and 3 mg/kg to Sprague-Dawley (SD) rats and at 3 and 10 mg/kg to F344 rats. In SD rats, the correlation coefficient on histopathology between the right and left kidneys was 0.7826 and remained within a lower range of strong correlation (range: ±0.7 ∼ ±0.9). The correlation coefficient between body-weight gains, urinary volume, osmolarity, serum blood urea nitrogen (BUN), creatinine, and relative kidney weights and renal histopathology was -0.6648, 0.7896, -0.7751, 0.8195, 0.8479, and 0.8969, respectively, showing a strong correlation, except a moderate correlation in body-weight gains (range: ±0.4 ∼ ±0.7). In F344 rats, the correlation coefficient on histopathology between the right and left kidneys was 0.8637, remaining within an upper range of strong correlation. The correlation coefficient between the above parameters and renal histopathology was -0.8175, 0.8616, -0.9045, 0.9010, 0.8991, and 0.9524, respectively, showing an extremely strong correlation in urinary osmolarity, serum BUN, and relative kidney weights (range: ±0.9 ∼ ±1.0). Therefore, the present study suggests that FYX-051-induced nephrotoxicity may occur with more inconsistency in the degree of nephropathy between the right and left kidneys in SD rats than in F344 rats, which would explain the above outcomes.
authors.affiliation: Research Laboratories, Fuji Yakuhin Co., Ltd., Saitama, Japan. t-shimo@fujiyakuhin.co.jp
authors.forename: Takeo
authors.initials: T
authors.lastname: Shimo
authors.forename: Mitsuyoshi
authors.initials: M
authors.lastname: Moto
authors.forename: Naoki
authors.initials: N
authors.lastname: Ashizawa
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Oba
authors.forename: Osamu
authors.initials: O
authors.lastname: Nagata
mesh_terms: D000818:Animals; D003460:Crystallization; D004791:Enzyme Inhibitors / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D008297:Male; D009570:Nitriles / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects; D011725:Pyridines / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D018675:Toxicity Tests; D016482:Urinalysis; D015430:Weight Gain; D019820:Xanthine / Q000378:metabolism*; D014968:Xanthine Dehydrogenase / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D009570:Nitriles; D011725:Pyridines; C504882:FYX-051; D019820:Xanthine; D014968:Xanthine Dehydrogenase