Diuretic-induced uricosuria: interaction with pyrazinoate transport in man

We investigated the acute effect of an orally administered uricosuric natriuretic agent (SKF-62698) on renal urate transport in paired clearance studies in seven normal men. The participants received SKF-62698 on two separate occasions. Prior to the second study, each received pyrazinamide (PZA) in order to inhibit the tubular secretion of urate. Within 3 hours, SKF-62698 significantly decreased the plasma urate and trebled the rate of urate excretion in the studies without PZA. In contrast, after PZA pretreatment. SKF-62698 did not diminish the plasma urate appreciably and elicited only 60% of the previous increase in urate excretion. Sodium excretion quadrupled after SKF-62698, irrespective of the presence of PZA. Plasma concentrations of pyrazinoate, the renally active metabolite of PZA, were at levels previously shown in the chimpanzee to primarily inhibit the tubular secretion of urate. Therefore, intact tubular secretion of urate probably was necessary in order for SKF-62698 to elicit its maximum uricosuric response. SKF-62698 appeared to inhibit the tubular secretion of pyrazinoate, but the observed changes in urate transport could not be explained on that basis.