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ToxSci Advance Access published online on June 2, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi210
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received April 14, 2005
Accepted May 19, 2005

Biotransformation and Toxicokinetics

Simultaneous Treatment with Citrate Prevents Nephropathy Induced by FYX-051, a Xanthine Oxidoreductase Inhibitor, in Rats

Takeo Shimo 1*, Naoki Ashizawa 1, Koji Matsumoto 1, Takashi Nakazawa 1, and Osamu Nagata 1

1 Research Laboratories 2, Fuji Yakuhin Co., Ltd., 636-1 Iidashinden, Nishi-ku, Saitama 331-0068, Japan

* To whom correspondence should be addressed.
Takeo Shimo, E-mail: t-shimo{at}fujiyakuhin.co.jp


  Abstract

The possible mechanism of the underlying nephropathy found in the rat toxicity study of FYX-051, a xanthine oxidoreductase inhibitor, was investigated. Rats received oral treatment of either 1 or 3 mg/kg of FYX-051, with and without citrate for 4 weeks to elucidate whether nephropathy could be caused by materials deposited in the kidney. Furthermore, analysis of the renal deposits in rats was also performed. Consequently, interstitial nephritis comprising interstitial inflammatory cell infiltration, dilatation, basophilia and epithelial necrosis of renal tubules and collecting ducts, deposits in renal tubules and collecting ducts, and so forth was seen in 6 of the 8 rats and in all the 8 rats in the 1 and 3 mg/kg FYX-051 alone groups, respectively, with the intensity in the 3 mg/kg group being moderate to severe. In the simultaneous treatment with citrate group, however, no alterations were observed in the kidney, except for minimal interstitial nephritis in one instance in the 3 mg/kg FYX-051 + citrate group along with an increased urinary pH, leading to an increase in xanthine solubility. Analysis of intrarenal deposits showed that the entity would be composed of xanthine crystals. The present study, therefore, showed that nephropathy in rats occurring after the administration of FYX-051 was a secondary change caused by xanthine crystals being deposited in the kidney, and no other causes could be implicated in this kidney lesion.

Keywords: FYX-051; citrate; xanthine oxidoreductase inhibitor; xanthine crystals; nephropathy; rats.
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Home page
 Toxicol PatholHome page
T. Shimo, N. Ashizawa, M. Moto, K. Matsumoto, T. Iwanaga, and O. Nagata
FYX-051, a Xanthine Oxidoreductase Inhibitor, Induces Nephropathy in Rats, but not in Monkeys
Toxicol Pathol, June 1, 2009; 37(4): 438 - 445.
[Abstract] [Full Text] [PDF]


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