Uricosuria probenecid

The tubular secretion of penicillin is inhibited by probenecid, so that the blood concentration and its half life (therapeutic effects) is prolonged with the simultaneous use of these two drugs. Phenylbutazone can block the renal tubular reabsorption of uric acid, leading to uricosuria. 

A uricosuric and renal tubular-blocking agent, probenecid inhibits the tubular resorption of urate, thus increasing the urinary excretion of uric acid and decreasing serum uric-acid levels. Effective uricosuria reduces the miscible urate pool, retards urate deposition, and promotes resorption of urate deposits. 

No. Methotrexate increases serum uric acid, and concurrent therapy with probenecid results in increased uricosuria. The levels of methotrexate may also be increased, through competition with probenecid for the organic acid secretory system. The probability of methotrexate-induced uric acid neuropathy is increased by the administration of probenecid. 

Low doses (1 or 2 g/day) can decrease urate excretion and elevate plasma urate concentrations intermediate doses (2 or 3 g/day) may not alter urate excretion large doses (more than 5 g/day) induce uricosuria and lower plasma urate levels. However, such large doses are tolerated poorly. Even small doses of salicylate can block the effects 0/probenecid and other uricosuric agents that decrease tubular reabsorption of uric acid. 

Meisel AD, Diamond HS. Mechanism of probenecid-induced uricosuria inhibition of reabsorption of secreted urate. Arthritis Rheum (1977) 20, 128. 

The patient was placed on an essentially purine-free diet and received no medication for 5 days. Uric acid metabolism disclosed uricemia 2.0 mg/dl uricosuria 510 mg/day Cur 15.4 ml/min Ccr 91 ml/min fractional excretion of uric acid (Cur/Ccr) 16.9%. Basal plasma calcitonin was 168 pg/ml (normal values undetectable). A pentagastrin bolus injection of 0.5 g/Kg elevated plasma calcitonin over 1000 pg/ml. Simultaneously, serum uric acid decreased from 2.0 mg/dl to 1.3 mg/dl, and Cur/Ccr increased from 16.9% to 25.7%. A pentagastrin test in two control subjects did not make plasma calcitonin levels detectable, nor did it modify uric acid excretion. Her clinical course was progressively down-hill and she died after several bronchoneumonic episodes and massive tracheal hemorrage. Pyrazinamide and probenecid tests could not be done. Permission for autopsy was denied. 

Uricosuria was established in six sxabjects by the oral administration of probenecid 2g daily. The acute oral administration of pyrazinamide 3g during probenecid uricosuria decreased urate excretion from a mean of 463 72 [igm/min when probenecid alone was given to 135 21 j.gm/min when probenecid was given with pyrazinamide (p <. 01). Pyrazinamide administration reversed probenecid uricosuria, resulting in urate excretion which was less than control urate excretion when no drug was administered. 

The decrement in urate excretion produced by pyrazinamide was more pronounced when profound uricosuria was induced by oral administration of a single 2 gram dose of probenecid. Urate... 

Alternative interpretations of these results appear less probable. Pyrazinamide, or its active metabolite, pyrazinoic acid, might competitively inhibit the effect of probenecid cuid sulfinpyrazone on urate reabsorption. Since the ability to suppress probenecid or sulfinpyrazone induced uricosuria is shown by several drugs which inhibit urate secretion, including aspirin, pyrazinamide, and lactate, the proposal of cin additional effect for these drugs is uneconomical. Moreover, this competitive inhibition of drug effects does not explain the apparent excessive urate secretion (as measured by pyrazinamide suppression) observed when uricosuria resulted from water diuresis. 

The pyrazinamide suppression test underestimates urate secretion. Uricosuria induced by probenecid and sulfinpyrazone appears to represent, at least in part, inhibition of post-secretory urate reabsorption. 

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