In the initial phase of clinical studies, it was shown that
E3040, a new type of anti-inflammatory
drug, reduced plasma
uric acid levels. The present study describes a comparison of the excretion of
uric acid in the proximal tubules of the kidney after administration of
E3040 and its conjugates, sulphate and
glucuronide, with that of other general
uricosuric agents in DBA/2N mice. The aim of this investigation was to elucidate the mechanism for the uricosuric action of
E3040. It was found that
E3040 increased the excretion rate of
uric acid in a dose-dependent manner, and the excretion rates following 10 and 50 mg/kg doses were significantly greater than that of the control group. The paradoxical effect observed with
probenecid was not seen in the
E3040 dose-response curve for the
uric acid excretion rate. Neither E3040-sulphate nor E3040-glucuronide increased the excretion rate of
uric acid significantly, even at a high dose, such as 200 mg/kg. In the
pyrazinoic acid suppression test, the
uric acid excretion rate after concomitant administration of
E3040 and
pyrazinoic acid was significantly higher than that after administration of
pyrazinoic acid alone, and the rate after concomitant administration was 30% of the level after administration of
E3040 alone. The change in the excretion rate of
uric acid after concomitant administration of
E3040 and
pyrazinoic acid was similar to that of AA193, a selective inhibitor of the presecretory reabsorption of
uric acid. From these results, it appears that
E3040 may exert its uricosuric action by reducing the presecretory reabsorption of
uric acid rather than increasing its secretion.