Pyrazinamide Probenecid

PROBENECID PYRAZINAMIDE 1 efficacy of antigout drugs Pyrazinamide can induce hyperuricaemia Pyrazinamide should not be used in patients with gout... 

Most drugs act by reducing active transport rather than by enhancing it. Thus, drugs that promote uric acid loss (uricosuric agents, such as probenecid and sulfinpyrazone) probably inhibit active urate reabsorption, while pyrazinamide, which reduces urate excretion, may block the active tubular secretion of uric acid. A complicating observation is that a drug may primarily inhibit active reabsorption at one dose and active secretion at another, frequently lower, dose. For example, small amounts of salicylate will decrease total urate ex-... 

C. Pyrazinamide is known to cause hyperuricemia and precipitate gouty arthritis. Pyrazinamide-induced gouty arthritis does not respond to uricosuric therapy with probenecid but may respond to acetylsalicylic acid. Cycloserine (A) can cause headaches, confusion, tremors, and seizures, possibly secondary to low levels of magnesium in the cerebrospinal fluid cycloserine should be avoided in patients with epilepsy and mental depression. It is not associated with hyperuricemia. Thiacetazone (B) is an antibiotic that is rarely used in tuberculosis. The most common adverse reactions are general rashes and GI intolerance. Its use is not associated with hy-... 

Pyrazinamide commonly causes hyperuricaemia and may therefore reduce the uricosuric effect of benzbromarone and probenecid. Allopurinol is unlikely to be effective against pyrazinamide-induced hyperuricaemia, and may exacerbate the situation, whereas benzbromarone may have modest efficacy in reducing hyperuricaemia caused by pyrazinamide. 

The likely overall effect is that if probenecid were to be used to treat the hyperuricaemia caused by pyrazinamide, the normal uricosuric effects of probenecid would be diminished, and larger doses would be required. However, see above, for advice relating to hyperuricaemia caused by pyrazinamide. 

The investigation was conducted with the voluntary cooperation of 10 normal males (mean age, 33 years) who were placed on an essentially purine-free diet during the study. Renal handling of uric acid was examined by means of the pyrazinamide (PZA) and probenecid (PB) tests, performed in three uricemia states normouricemia 3.6 to 6.4 mg/dl), allopurinol-induced hypouricemia (under 3.5 mg/dl), and hyperuricemia after oral administration of RNA monosodium salt (over 6.5 mg/dl). 

Fifty patients (22 males and 28 females mean age 46 years) were consecutively referred to our Metabolic Unit for the evaluation of recurrent nephrolithiasis. Diagnosis was made on the basis of spontaneous emission or chirurgical extraction of two or more calculi with an interval superior to one year. In every patient we performed a metabolic study and the results were compared with those obtained in 20 controls (10 males and 10 females mean age 33 years) Hyperuricosuria was defined as daily uric acid excretion above 800 mg for men and 750 mg for woman, while on a purine-free diet. Renal handling of uric acid ms evaluated by means of pyrazinamide (PZA) and probenecid (PB) tests. ... 

RENAL HANDLING OF URIC ACID IN GOUT BY BffiANS OF THE PYRAZINAMIDE AND PROBENECID TESTS... 

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. 

The results obtained by studying the effect of probenecid on the clearance of urate were consistent with the pyrazinamide test, indicating defective renal tubular reabsorption of urate. Administration of probenecid, which normally increases the urate clearance by two to five- fold (7), affected the uric acid clearance in the patient only slightly, increasing it from 55.3 ml/minute to 74.8 ml/minute. The ratio of the urate clearance to the inulin clearance increased from 65% to 84%. 

To test the hypothesis that part or all of renal tubular reabsorption of urate occurs distal to urate secretion, pyrazinamide suppression tests were carried out after inhibition of urate reabsorption. Probenecid or sulfinpyrazone was used to block urate reabsorption. 

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... 

Neither probenecid nor pyrazinamide significantly altered uric acid excretion when administered to patients with serum salicylate levels above 14 mg%. 

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. 

---