Mechanism of the uricosuric action of the anti-inflammatory drug E3040 used to treat inflammatory bowel disease I: study using a rat model of hyperuricemia.
E3040, a new class of anti-inflammatory drug, was found to reduce the plasma uric acid level in the first phase of clinical studies. In the present study, the mechanism of the uricosuric action of E3040 was investigated using the hyperuricemia model rat. The fractional excretion of uric acid (FEurate), an indicator of the excretion of uric acid in the renal tubules, at 30, 60 and 90 min after administration of E3040 (50 mg kg(-1)) was significantly elevated as compared with that in the control. This elevation of the FEurate by E3040 was dose-dependent. Although the FEurate was elevated spontaneously 30 min after administration of E3040-sulfate (E-Sul) and glucuronide (E-Glu) (100 mg kg(-1), respectively), the value was not significantly different from the control. Based on these results, it was suggested that E3040 has a uricosuric action, probably in the proximal tubules, and the uricosuric action after administration of E3040 may be mainly due to the parent drug. Concerning the tissue distribution, the kidney concentration of E-Sul after i.v. administration of the E3040 (50 mg kg(-1)) was higher than that of the parent drug (kidney/plasma ratio approximately 2).
Yamada
H
H
Department of Pharmacy, The University of Tokyo Hospital, The University of Tokyo, Japan. hami-tky@umin.ac.jp
Kotaki
H
H
Furitsu
H
H
Sawada
Y
Y
Iga
T
T
D000818:Animals; D052160:Benzothiazoles; D004195:Disease Models, Animal; D015212:Inflammatory Bowel Diseases / Q000097:blood / Q000188:drug therapy* / Q000652:urine; D007444:Inulin / Q000493:pharmacokinetics; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D011725:Pyridines / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013844:Thiazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors; D014527:Uric Acid / Q000097:blood* / Q000652:urine; D014528:Uricosuric Agents / Q000493:pharmacokinetics / Q000494:pharmacology*
D052160:Benzothiazoles; D016859:Lipoxygenase Inhibitors; D011725:Pyridines; D013844:Thiazoles; D014528:Uricosuric Agents; C095803:E 3040; D014527:Uric Acid; D007444:Inulin; D013930:Thromboxane-A Synthase