Pyrazinamide suppression test

Attempshave been made to evaluate the impotance of the secretory transport of urate in man by using pharmacologic agents. A pyrazinamide suppression test was developed by Steele and Rieselbach (1967). 

A pyrazinamide suppression test (Table l) indicated defective renal tubular reabsorption of urate. The clearance of urate and the ratio of the urate clearance... 

We were able to conduct three different studies of agents which interfere with renal transport of urate during continuous inulin infusions. The first such study (a pyrazinamide suppression test), is shown on the next slide. The data from these experiments will be shov/n as the ratio of urate clearance to inulin clearance. A ratio greater than 1.0 reflects tubular secretion while a lower ratio would suggest reabsorption. The time of day is on the horizontal axis labelled "hours". 

In 1961 Gutman and Yu proposed a three component system for the regulation of the renal excretion of uric acid in man. The first component of this system is filtration of plasma urate at the glomerulus. While this process is certain to be operative in the human kidney, its quantitative role in the renal excretion of uric acid in man depends upon the extent of urate binding to plasma proteins in vivo. This is a subject that is being discussed in another section of this symposium and will not be considered further in this paper. The second and third component of this system relate to uric acid reabsorption and secretion by the human nephron. Ample data is available to document that both of these processes are operable in the human kidney (Gutman and Yu, 1957 Gutman, et al., 1959), but the relative contribution of each to the final excretion of uric acid has been difficult to determine with conventional clearance techniques. However, a potential solution to this problem of bidirectional uric acid transport appeared in 1967 when Steele and Rieselbach introduced the "pyrazinamide suppression test . 

Since there was no data available in 1967 which conflicted with these assumptions, the "pyrazinamide suppression test" appeared to be a useful clinical tool for quantitating uric acid secretion and reabsorption in man. However, recent studies of pyrazinamide and uric acid handling by the kidney provide data that have led us to question all three of the assumptions underlying the "pyrazinamide suppression test" (Holmes, Wyngaarden, and Kelley, 1972). Therefore, we would like to consider each assumption and the data relevant to it. 

In the next paper on this program Dr. Diamond and colleagues will present data supporting a model for a post-secretory reabsorptive site for uric acid in man. In view of this conflicting data and the absence of any direct data that indicates uric acid secretion occurs at a site totally distal to reabsorption in the human nephron, we believe that assumption number one of the pyrazinamide suppression test as it now stands, cannot be validated. 

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. 

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. 

The test is performed by determining uric acid excretion before and after the administration of pyrazinamide or its metabolite pyrazinoic acid (PZA) in a dosage sufficient to give maximal suppression of uric acid excretion. The decrement in uric acid excretion after PZA administration is taken as a quantitative measure of uric acid secretion. In addition the difference between filtered load of uric acid and uric acid excretion at the time of maximal PZA effect is taken as a quantitative measure of uric acid reabsorption. These estimates of uric acid secretion and reabsorption assume the following conditions (Table 1) ... 

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