A selective uricosuric action of AA-193 in rats. Comparison with its effect on PAH secretion in vivo and in vitro.
We evaluated the uricosuric action of AA-193 by comparing it with the effect on PAH secretion in rats, using in vivo and in vitro techniques. The i.v. administration of AA-193 elevated the fractional excretion of urate (FEurate) significantly in a dose-dependent manner at doses from 0.1 to 10 mg/kg. Only at the highest dose of 10 mg/kg did AA-193 cause a momentary decrease in FEPAH. On the other hand, tienilic acid and probenecid reduced FEPAH at uricosuric effective doses. To compare the inhibitory effects of uricosurics on urate reabsorption and PAH secretion more directly, we investigated the effects of uricosurics on the OH- gradient-dependent urate uptake in brush border membrane vesicles and the net PAH accumulation in cortical slices. The relation between the affinity of uricosuric drug for urate and PAH transporters corresponds well with the difference between the effect on FEurate and that on FEPAH. The relative affinity of AA-193 for the urate uptake is 83-fold greater than that for the PAH accumulation. These results support the assumption that, in contrast with the other uricosurics, AA-193 has a much higher affinity for urate reabsorption system than that for the common pathway of weak organic acids in rats.
Dan
T
T
Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co. Ltd., Shizuoka, Japan.
Onuma
E
E
Tanaka
H
H
Koga
H
H
D000818:Animals; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000494:pharmacology*; D007668:Kidney / Q000098:blood supply; D008297:Male; D008871:Microvilli / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012079:Renal Circulation / Q000187:drug effects; D013989:Ticrynafen / Q000652:urine; D014527:Uric Acid / Q000378:metabolism; D014528:Uricosuric Agents; D010130:p-Aminohippuric Acid / Q000378:metabolism / Q000652:urine*
D007555:Isoxazoles; D014528:Uricosuric Agents; C062919:AA 193; D014527:Uric Acid; D013989:Ticrynafen; D010130:p-Aminohippuric Acid