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Uricosuric agents decrease the plasma urate level in rats by concomitant treatment with topiroxostat, a novel

Tetsuya Taniguchi1, Naoki Ashizawa1, Koji Matsumoto1

  • 1Research Laboratories 2, Fuji Yakuhin Co., Ltd., Saitama, Nishi-ku, Japan.

The Journal of Pharmacy and Pharmacology
|November 22, 2015
PubMed
Abstract

Insights

A new rat model using topiroxostat effectively evaluates hypouricemic agents by modulating urate formation. This model is sensitive to urate production rates, offering a valuable tool for drug development.

Area of Science:

  • Pharmacology
  • Biochemistry
  • Drug Discovery

Background:

  • Gout and hyperuricemia are linked to elevated plasma urate levels.
  • Uricosuric agents aim to reduce plasma urate by increasing its excretion.
  • Developing reliable preclinical models is crucial for evaluating hypouricemic drug efficacy.

Purpose of the Study:

  • To establish a rat model for assessing the hypouricemic effects of uricosuric agents.
  • To investigate the influence of urate formation rate on the efficacy of uricosuric drugs.
  • To validate the use of topiroxostat in a preclinical model for gout therapeutics.

Main Methods:

  • Rats were induced hyperuricemic using potassium oxonate (uricase inhibitor) or hypouricemic using topiroxostat (xanthine oxidoreductase inhibitor).
  • Uricosuric agents (FYU-981, F12859, probenecid) were administered to rats under different conditions.
  • Co-administration of topiroxostat with inosine (urate precursor) was performed to assess its impact.

Main Results:

  • Uricosuric agents showed no hypouricemic effect in potassium oxonate-induced hyperuricemic rats.
  • In topiroxostat-treated rats, uricosuric agents significantly reduced plasma urate levels in a dose-dependent manner.
  • Co-treatment with inosine abolished the hypouricemic effect of uricosuric agents in topiroxostat-treated rats.

Conclusions:

  • The efficacy of uricosuric agents is influenced by the rate of urate formation.
  • Topiroxostat-induced reduction in urate formation creates a suitable model for evaluating hypouricemic agents in rats.
  • This model offers a valuable platform for preclinical assessment of drugs targeting hyperuricemia.
Keywords:
probenecidtopiroxostaturateuricosuric agentxanthine oxidoreductase inhibitor

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