AND THE ACTIONS OF URICOSURIC DRUGS

A B S T R A C T These experiments were designed to define the renal disposition of pyrazinoic acid in a nonhuman primate that is phylogenetically close to man and to relate this to the effects of pyrazinoate on urate excretion. The renal clearance of pyrazinoate was -almost always greater than the simultaneous glomerular filtration rate at plasma concentrations ranging from 1.9 to 960 Fg/ml. Some inhibitors of tubular secretion, probenecid, MK-282 (an experimental, potent uricosuric drug), p-aminohippurate, iodopyracet, sulfinpyrazone, and mersalyl, reduced clearances of pyrazinoate to values far below filtration rate. Chlorothiazide, allopurinol, and salicylate did not. The clearance of pyrazinoate was not influenced by changes in urine flow. It is concluded that pyrazinoate is actively secreted and actively reabsorbed. Pyrazinoate had a dual effect on urate excretion. At concentrations in plasma less than 10 ug/ml there was a concentration related fall in urate/inulin clearance ratio, reaching values of 10-20% of control. Over the range of 10-100 Ihg/ml in plasma, the clearance of urate remained maximally depressed. At higher concentrations of pyrazinoate there was a concentration related increase in urate/inulin clearance ratio such that at pyrazinoate levels above 600 /tg/ml a definite uricosuric response was obtained. Prior administration of pyrazinoate to give plasma levels of 20-140 /Ag/ml completely or almost completely prevented uricosuric respones to probenecid, PAH, chlorothiazide, and sulfinpyrazone. lodopyracet, mersalyl, salicylate and N-acetyl-4-dibutylsulfamoyl-3trifluoromethylbenzenesulfonamide (MK-282) retained