Studies on Uric Acid Clearance in Urate Oxidase Inhibitor-Treated Rat

A method for determining uric acid clearance to evaluate uricosuric drugs was planned with urate oxidase inhibitor-treated rats. The metabolism of uric acid to allantoin in the animals was inhibited by administration of potassium oxonate 250 mg/kg i. p. twice with a 2-hour interval. Five 20-minute clearance experiments on uric acid and inulin were successively done from 40 minutes after the second administration of potassium oxonate und er anesthesia with urethane. Test drugs were given i. p. just after the first urine collection. Under the experimental conditions, th e animals showed well-controlled levels of urine volume, urineexcreted amount of uric acid, plasma uric acid, inulin clearance and uric acid clearance, and the fractional excretion of uric acid was nearly 0.6. The free-type ratio of plasma uric acid in the animals was 97%, and hence the fractional excretion supported the reabsorptive net flux of uric acid in the tubules. Uricosuric agents, probenecid and tienilic acid increased the urine-excreted amount of uric acid with an obvious elevation o f fractional excretion of uric acid. A high dose of furosemide, which had been reported to inhibit the tubular secretion of uric acid, decreased the fractional excretion of uric acid with a rise of plasma uric acid. Thiazide diuretics such as trichloromethiazide and hydrochlorothiazide also increased the urine-excreted amount of uric acid together with increases of urine volume and fractional excretion of uric acid. These-results agree well with the characteristics of the drugs used. No practical procedure has been available for evaluating uricosuric drugs by animal experiments, except for those using primates such as chimpanzees and cebus monkeys, because of species differences in the metabolism and excretion of uric acid. Thus, the method proposed here with a commonly used animal is very practical and useful. However, although the cause is not clear, uricosuric drugs such as probenecid and tienilic acid obviously increased plasma uric acid during the clearance experiment. This was an unexpected effect from the clinical view point of the drugs and needs to be studied further.