Tanaka S, Kanda A, Ashida S
Research Institute, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.
Jpn J Pharmacol. 1990 Nov;54(3):307-14. doi: 10.1254/jjp.54.307.
The purpose of this study was to evaluate the uricosuric and diuretic properties of the new diuretic agent DR-3438. In the conventional clearance studies in urate-loaded dogs, intravenous injection of DR-3438 (3-30 mg/kg) resulted in dose-related increases in fractional excretion of urate (FEua), urine flow and sodium excretion. At doses causing similar natriuresis, tienilic acid (50 mg/kg, i.v.) markedly increased the FEua value, whereas indacrinone (1 mg/kg, i.v.) had no significant effect on it. Trichloromethiazide (1 mg/kg, i.v.) and furosemide (0.3 mg/kg, i.v.) tended to decrease the FEua. Thus, the uricosuric activity of DR-3438 (30 mg/kg) was 0.6-fold that of tienilic acid and 3.4-fold that of indacrinone. In contrast, in urate-loaded rabbits that exhibit net tubular secretion of urate, intravenous DR-3438 (30 mg/kg) produced a significant decrease in FEua. Stop-flow studies in dogs revealed that DR-3438 (30 mg/kg) blocks both urate reabsorption and p-aminohippurate secretion in the proximal segment of the nephron and strongly inhibits reabsorption of water, sodium and potassium in the distal segments. These results suggest that DR-3438 exerts uricosuric activity through blocking urate transport in the proximal tubules and diuretic and saluretic activities by inhibiting water and sodium reabsorption in the distal segment of the nephron.
本研究的目的是评估新型利尿剂DR - 3438的促尿酸排泄和利尿特性。在给尿酸负荷犬进行的传统清除率研究中，静脉注射DR - 3438（3 - 30毫克/千克）导致尿酸排泄分数（FEua）、尿流量和钠排泄呈剂量相关增加。在引起相似利钠作用的剂量下，替尼酸（50毫克/千克，静脉注射）显著增加FEua值，而茚达立酮（1毫克/千克，静脉注射）对其无显著影响。三氯噻嗪（1毫克/千克，静脉注射）和呋塞米（0.3毫克/千克，静脉注射）倾向于降低FEua。因此，DR - 3438（30毫克/千克）的促尿酸排泄活性是替尼酸的0.6倍，茚达立酮的3.4倍。相比之下，在表现出尿酸净肾小管分泌的尿酸负荷兔中，静脉注射DR - 3438（30毫克/千克）使FEua显著降低。犬的停流研究表明，DR - 3438（30毫克/千克）可阻断肾单位近端段的尿酸重吸收和对氨基马尿酸分泌，并强烈抑制远端段的水、钠和钾重吸收。这些结果表明，DR - 3438通过阻断近端小管的尿酸转运发挥促尿酸排泄活性，并通过抑制肾单位远端段的水和钠重吸收发挥利尿和促钠排泄活性。
