Dan T, Yoneya T, Onoma M, Onuma E, Ozawa K
Shizuoka Fuji Gotemba Research Laboratories, Chugai Pharmaceutical, Tokyo, Japan.
Metabolism. 1994 Jan;43(1):123-8. doi: 10.1016/0026-0495(94)90167-8.
In normal rats, consecutive administrations of AA-193 for 7 days maintained the dose-dependent uricosuric activity without significant changes of the plasma urate level. In clearance studies, AA-193 produced an increase in the fractional excretion of urate (FEua) namely an inhibition of the net urate reabsorption in the nephron, which was probably dependent on the plasma concentration of the agent. During in vitro studies, 1 mmol/L AA-193 had no effect on liver uricase activity and 0.2 mmol/L AA-193 did not inhibit xanthine dehydrogenase activity. Therefore, it is unlikely that AA-193 at physiologic doses has a significant effect on either the production or degradation of urate. To assess the hypouricemic effect of AA-193 derived from its uricosuric effect, we used uricase-inhibited rats produced by oxonate feeding. In the hyperuricemic rat model, consecutive administrations of AA-193 for 7 days increased urate excretion and decreased the plasma urate level. We conclude that AA-193 has a hypouricemic effect caused by increases in urate excretion in hyperuricemic rats.
在正常大鼠中，连续7天给予AA - 193可维持剂量依赖性的促尿酸尿活性，而血浆尿酸水平无显著变化。在清除率研究中，AA - 193使尿酸分数排泄（FEua）增加，即抑制了肾单位中尿酸的净重吸收，这可能取决于该药物的血浆浓度。在体外研究中，1 mmol/L的AA - 193对肝脏尿酸酶活性无影响，0.2 mmol/L的AA - 193不抑制黄嘌呤脱氢酶活性。因此，生理剂量的AA - 193对尿酸的产生或降解不太可能有显著影响。为了评估源自其促尿酸尿作用的AA - 193的降尿酸作用，我们使用了通过饲喂氧嗪酸盐产生的尿酸酶抑制大鼠。在高尿酸血症大鼠模型中，连续7天给予AA - 193可增加尿酸排泄并降低血浆尿酸水平。我们得出结论，AA - 193在高尿酸血症大鼠中具有由尿酸排泄增加引起的降尿酸作用。
