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Enhancement of pharmacological effects of uricosuric agents by concomitant treatment with pyrazinamide in rats

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Abstract

Our goal was to establish a model for the evaluation of the effects of uricosuric agents and to clarify the underlying mechanism(s). The effects of a uricosuric agent co-treated with pyrazinamide, an anti-tubercular agent, on urate handling were examined in rats. Furthermore, the effects of uricosuric agents on urate uptake were evaluated using the vesicles of rat renal brush-border membrane. Treatment with probenecid, at a dose of 100 mg/kg, significantly increased the urinary urate to creatinine ratio (UUA/UCRE) in pyrazinamide-treated rats although the same treatment did not produce any uricosuric effects in intact rats. In this model, the urinary excretion of pyrazinecarboxylic acid (PZA), an active metabolite of pyrazinamide, was decreased by probenecid and indicated an inverse correlation between urinary excretion of urate and PZA. Furthermore, in the examination using FYU-981, a potent uricosuric agent, a more than 10-fold leftward shift of the dose–response relationship of the uricosuric effect was observed in pyrazinamide-treated rats when compared with intact rats. In the in vitro study, the treatment of the vesicles of rat renal brush-border membrane with PZA produced an increased urate uptake, which was inhibited by uricosuric agents. The pyrazinamide-treated model used in the present study seems to be valuable for the evaluation of uricosurics because of its higher sensitivity to these drugs when compared to intact rats, and this is probably due to the enhanced urate reabsorption accompanied with trans-stimulated PZA transport at the renal brush-border membrane.

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Abbreviations

ANOVA:

Analysis of variance

FEUA :

Fractional excretion of urate

HPLC:

High-performance liquid chromatography

MC:

Methylcellulose

PUA :

Plasma urate level

PZA:

Pyrazinecarboxylic acid

UUA :

Urinary urate level

UCRE :

Urinary creatinine level

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Authors and Affiliations

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

    Tetsuya Taniguchi, Naoki Ashizawa, Koji Matsumoto & Takashi Iwanaga

Authors
  1. Tetsuya Taniguchi
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  2. Naoki Ashizawa
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  3. Koji Matsumoto
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  4. Takashi Iwanaga
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Corresponding author

Correspondence to Tetsuya Taniguchi.

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Funding

This research was supported by Fuji Yakuhin Co., Ltd.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving animal were in accordance with the ethical standards of the Animal Care and Utilization Guidelines of Fuji Yakuhin Research Laboratories.

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Fig. S1.

Pharmacokinetics of pyrazinamide and PZA after administration of pyrazinamide to rats. Data are represented as the mean + standard deviation (n = 3) (GIF 6 kb)

High Resolution Image (TIFF 26 kb)

Fig. S2.

Pharmacokinetics of urinary FYU-981 (a) or probenecid (b) to creatinine ratio in pyrazinamide-treated rats. Experiment was performed according to the protocol C in Fig. 1. Data are represented as the mean + standard deviation (n = 4) (GIF 12 kb)

High Resolution Image (TIFF 48 kb)

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Taniguchi, T., Ashizawa, N., Matsumoto, K. et al. Enhancement of pharmacological effects of uricosuric agents by concomitant treatment with pyrazinamide in rats. Naunyn-Schmiedeberg's Arch Pharmacol 390, 253–260 (2017). https://doi.org/10.1007/s00210-016-1324-5

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  • DOI: https://doi.org/10.1007/s00210-016-1324-5

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