The development of isotopic technics provided the means for an accurate assessment of the role of uricolysis in man.Ever since the first pool and turnover studies by Benedict, Forsham and Stettenl in 1949, a rather consistent discrepancy between the amount of uric acid calculated to be produced per day and the amount of uric acid actually found in the urine has been noted; and, perhaps more important, recovery studies2 have uniformly shown incomplete recovery of injected isotopically labeled uric acid in the urine.A few, but representative, data from approximately one hundred uric acid pool and turnover studies carried out in our laboratory are given in Figure 40, which shows the cumulative recovery of intravenously injected uric a~i d -2 -C~~ from the urine of 13 individuals. Three normal subjects excreted from 62.8 to 68.9 per cent of injected uric acid-C14 in urinary uric acid; these values are similar to those obtained by others. Three patients with primary gout, who were shown to have overproduction of uric acid and a rapid and exaggerated incorporation of glycine-C1* into urinary uric acid, excreted a similar proportion of administered uric acid in their urine. These patients were young subjects with recent onset of symptomatic gout. On the other hand, two gouty subjects with normal uric acid production and a normal pattern of glycine incorporation into uric acid excreted a smaller fraction of uric acid-CI4 in the urine-despite a normal glomerular filtration rate. These results lend support for a dual etiology of hyperuricemia in primary gout.

The origin of uric acid, metabolic pathways of purine metabolism and the disposition of uric acid in normal man are reviewed. Two thirds of the uric acid is normally excreted through the kidney while one third gains entrance to the gut where it undergoes uricolysis. The pathogenesis of hyperuricemia in primary and secondary gout is discussed. Increased production or decreased excretion of uric acid are the two principal mechanisms of hyperuricemia. The known biochemical defects associated with primary overproduction gout are outlined. Extrarenal uricolysis assumes a greater role when the renal excretion of uric acid is compromised.

SUMMARY Bidirectional renal urate transport was studied in both control and gouty subjects. 99-3 % of filtered urate undergoes reabsorption as assessed by pyrazinamide suppression of urate secretion. The maximum uricosuric response to benzbromarone, equated with the minimum secretory rate, amounted to 50% of the filtered load in normal persons and was lower in gouty normoproducers. Since benzbromarone selectively inhibits reabsorption of secreted urate, the difference between secreted and excreted uric acid becomes a valid measure of urate reabsorption distal to the secretory site and amounts to 80 % ofthe secretedload in both groups. These data conform to a 4-component model of renal urate handling in man.In normal man about two-thirds of uric acid is excreted in the urine. Until quite recently the '3-component mechanism' proposed by Gutman and Yu (1961) (Bennett et al., 1972;Wilson and Goldstein, 1973 varying from 2 4 mg/dl (0.14 mmol/l) to 24 mg/dl (1 42 mmol/l). In studies using the highest concentration of uric acid Krebs-Ringer phosphate solution was replaced by 0 -2 M Tris buffer, pH 7 4, in which urate remained soluble. After incubation for 12 hours aliquots were withdrawn from the sample and diffusate sides for assay of 14C and enzymatic determination of urate.The reabsorption of filtered urate was determined in 10 healthy subjects who had been given PZA to inhibit tubular secretion of uric acid. Urinary uric acid was determined in the 12 hour period between 3 and 15 hours after oral intake of 4 g of PZA. Reabsorbed uric acid was calculated as the difference between filtered and excreted uric acid.Tubular secretory rate of urate was assessed in 8 healthy volunteers and in 12 patients with primary gout, all of whom had normal glomerular filtration rates. In the gouty group 3 patients were overproducers of uric acid, while 9 patients had normal production of urate but low urinary uric acid excretion relative to their plasma urate levels. Adequate diuresis was accomplished with tap water given at '-hour intervals. Urine specimens were obtained by voiding at hourly intervals.After baseline values for plasma and urinary uric acid had been obtained 80 mg of micronised benzbromarone, a potent uricosuric drug, was given in a single oral dose (Sorensen and Levinson, 1976). Uric acid excretion was determined in each hourly fraction and expressed as Lg/minute (,mol/min) divided by the creatinine clearance to correct for differences in nephron mass. Maximum uricosuria was usually obtained during the fourth hour after benzbromarone administration. Urate excretion during maximum uricosuria related to the mean plasma urate concentration for that collection period becomes a measure of minimum secretion at a particular plasma urate concentration. Uric acid determinations were performed by the enzymatic spectrophotometric method of Praetorius (1949), while creatinine in serum and urine was assayed on an SMA660 (Terrytown, NY) (Chasson, et al., 1961). Medications were discontinued 14 days prior to all studies, which were ...

A B S T R A C T Certain gouty subjects with excessive de novo purine synthesis are deficient in hypoxanthineguanine phosphoribosyltransferase (HG-PRTase [EC 2.4.2.8]). The mechanism of accelerated uric acid formation in these patients was explored by measuring the incorporation of glycine-14C into various urinary purine bases of normal and enzyme-deficient subjects during treatment with the xanthine oxidase inhibitor, allopurinol.In the presence of normal HG-PRTase activity, allopurinol reduced purine biosynthesis as demonstrated by diminished excretion of total urinary purine or by reduction of glycine-'4C incorporation into hypoxanthine, xanthine, and uric acid to less than one-half of control values. A boy with the Lesch-Nyhan syndrome was resistant to this effect of allopurinol while a patient with 12.5% of normal enzyme activity had an equivocal response. Three patients with normal HG-PRTase activity had a mean molar ratio of hypoxanthine to xanthine in the urine of 0.28, whereas two subjects who were deficient in HG-PRTase had reversal of this ratio (1.01 and 1.04). The patterns of '4C-labeling observed in HG-PRTase deficiency reflected the role of hypoxanthine as precursor of xanthine. The data indicate that excessive uric acid in HG-PRTase deficiency is derived from hypoxanthine which is insufficiently reutilized and, as a consequence thereof, catabolized inordinately to uric acid. The data provide evidence for cyclic interconversion of adenine and hypoxanthine derivatives. Cleavage of inosinic acid to hypoxanthine via inosine does not contribute significantly to the formation of uric acid in either normal man or in patients with HGPRTase deficiency.

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