Hypouricemic and uricosuric actions of AA-193 in a hyperuricemic rat model.
In normal rats, consecutive administrations of AA-193 for 7 days maintained the dose-dependent uricosuric activity without significant changes of the plasma urate level. In clearance studies, AA-193 produced an increase in the fractional excretion of urate (FEua) namely an inhibition of the net urate reabsorption in the nephron, which was probably dependent on the plasma concentration of the agent. During in vitro studies, 1 mmol/L AA-193 had no effect on liver uricase activity and 0.2 mmol/L AA-193 did not inhibit xanthine dehydrogenase activity. Therefore, it is unlikely that AA-193 at physiologic doses has a significant effect on either the production or degradation of urate. To assess the hypouricemic effect of AA-193 derived from its uricosuric effect, we used uricase-inhibited rats produced by oxonate feeding. In the hyperuricemic rat model, consecutive administrations of AA-193 for 7 days increased urate excretion and decreased the plasma urate level. We conclude that AA-193 has a hypouricemic effect caused by increases in urate excretion in hyperuricemic rats.
Dan
T
T
Shizuoka Fuji Gotemba Research Laboratories, Chugai Pharmaceutical, Tokyo, Japan.
Yoneya
T
T
Onoma
M
M
Onuma
E
E
Ozawa
K
K
D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007555:Isoxazoles / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000502:physiology; D008099:Liver / Q000201:enzymology; D008297:Male; D010094:Oxonic Acid / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014503:Urate Oxidase / Q000032:analysis; D014527:Uric Acid / Q000097:blood* / Q000652:urine; D014528:Uricosuric Agents / Q000494:pharmacology*; D014968:Xanthine Dehydrogenase / Q000032:analysis
D007555:Isoxazoles; D014528:Uricosuric Agents; C062919:AA 193; D014527:Uric Acid; D010094:Oxonic Acid; D014968:Xanthine Dehydrogenase; D014503:Urate Oxidase