Study of the paradoxical effects of salicylate in low, intermediate and high dosage on the renal mechanisms for excretion of urate in man.

Salicylate administered to man in sufficiently large dosage (5 to 6 or more Gm. per day) causes marked uricosuria, characterized by substantially increased urate/inulin clearance ratios attributable to inhibition of tubular reabsorption of the filtered urate. In smaller dosage (1 to 2 Gm. per day) salicylate exerts a contrary effect, retention of urate, associated with lower than normal urate/inulin clearance ratios (1-8). When small doses of salicylate are given concurrently with probenecid, the retention of urate caused by the salicylate is sufficiently pronounced to counteract, to a marked degree, the uricosuric effect of the probenecid (9, 10). Phenylbutazone and phenylbutazone metabolite I similarly cause marked retention of urate when administered in low dosage (7), and are uricosuric in large dosage. Two explanations of this paradoxical effect have been offered (5, 7, 8). It is conceivable that the tubular transport system effecting reabsorption of urate might be stimulated by small doses and suppressed by larger doses of the drugs in question. Or, a postulated tubular excretory mechanism for urate (not apparent in the usual clearance measurements in man) might be inhibited by small doses, thus causing urate retention; and when larger doses are given tubular reabsorption of urate also is suppressed, the net effect then being uricosuric. The present study documents the paradoxical action of salicylate by providing more detailed data on the effect of small, intermediate and large doses on the 24 hour urinary urate excretion, using analytical methods incorporating precautions to obviate errors due to the presence