Mechanism of the uricosuric action of E3040, a drug used to treat inflammatory bowel disease II: study using DBA/2N mice.
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.
Yamada
H
H
Department of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 1080071, Japan. hami-tky@umin.ac.jp
Kotaki
H
H
Furitsu
H
H
Sawada
Y
Y
Iga
T
T
D000818:Animals; D052160:Benzothiazoles; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D011718:Pyrazinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D011725:Pyridines / Q000493:pharmacokinetics / Q000494:pharmacology*; D013844:Thiazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D014527:Uric Acid / Q000652:urine; D014528:Uricosuric Agents / Q000494:pharmacology*
D052160:Benzothiazoles; D005765:Gastrointestinal Agents; D011725:Pyridines; D013844:Thiazoles; D014528:Uricosuric Agents; C095803:E 3040; D014527:Uric Acid; D011718:Pyrazinamide; C005296:pyrazinoic acid