Uricosuric and diuretic activities of DR-3438 in dogs and rabbits.
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.
Tanaka
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S
Research Institute, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.
Kanda
A
A
Ashida
S
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D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D004232:Diuretics / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D007687:Kidney Tubules, Proximal / Q000187:drug effects*; D008297:Male; D009318:Natriuresis / Q000187:drug effects; D009399:Nephrons / Q000187:drug effects / Q000378:metabolism; D011817:Rabbits; D012964:Sodium / Q000652:urine; D014527:Uric Acid / Q000652:urine; D014528:Uricosuric Agents / Q000494:pharmacology*; D014563:Urodynamics / Q000187:drug effects
D001578:Benzopyrans; D004232:Diuretics; D014528:Uricosuric Agents; C067756:DR 3438; D014527:Uric Acid; D012964:Sodium