Study of the Paradoxical Effects of Salicylate in Low, Intermediate and High Dosage on the Renal Mechanisms for Excretion of Urate in Man *

Abstract

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 of a salicylate metabolite, gentisic acid. The relationships between the renal excretion of salicylate and of urate are then examined by means of simultaneous clearance techniques, including studies under conditions of urine pH made to vary from markedly acid to markedly alkaline. Clearance data on the antagonistic effect of small doses of salicylate on probenecid uricosuria, and vice versa, also are presented. Finally, the implications of the results as a whole are considered in relation to current concepts of renal mechanisms for the excretion of salicylate and of urate, with special reference to inferences regarding the possibility of tubular excretion of urate in man. METHODSThe subjects selected for investigation were all adult, gouty males, in the intercritical phase of the disorder. Forty-four studies were made in 23 of these subjects to determine the effect of orally administered acetylsalicylic acid, in divided doses totaling 1.0, 2.0, 3.0 and 5.2 Gm. per day, respectively, on the 24 hour urinary urate excretion and the serum urate level. All subjects were maintained on a constant diet low in purines and restricted in protein (60 to 75 Gm. per day) for at least three days preceding study. Twenty-four hour collections of urine were then made for eight or 12 days, blood samples being secured at appropriate intervals. After a four day control period, the patient received the prescribed daily medic...

Abnormal Renal Urate Homeostasis in Systemic Disorders

“…Renal excretion of urate is subject to considerable modification by varying concentrations of drugs in either blood or tubular fluid. These include salicylates [127], diuretics [34,115], uricosuric agents and many other drugs and will be dealt with in detail by other authors.…”

Gouty Arthritis in Acute Cerebrovascular Disease

“…A high dose of aspirin (>3 g/day) causes uricosuria, probably by inhibiting the tubular reabsorption of urate. However, a moderate dose of aspirin (1–2 g/day) may cause urate retention, possibly by inhibiting the tubular secretion of urate [40]. In a prospective study by Caspi et al [41], a low dose of aspirin (75–325 mg/day) was found to impair renal function and urate handling in elderly patients (age range: 61–94 years).…”

Renal Urate Excretion in Animal Models

“…If is of considerable interest that the rank order of response to mersalyl, chimpanzee >m an >Cebus monkey, is the same as that observed with other drugs. We have made extensive study of the responses to salicylates in Cebus monkeys and chimpanzees [unpub lished], When these data are compared to those of Yu and G utm a n [61] for man the above rank order was obtained. The foregoing holds true whether the comparisons are made in terms of drug concentrations in plasma, or in urine or in terms of dose (per kg).…”