Abstract
Inhibition of [14C]-urate uptake by uricosuric and antiuricosuric agents was investigated in human brush-border membrane vesicles, urate being transported either by anion exchange mechanisms or by voltage sensitive pathway. The IC50 for drugs on [14C]-urate uptake in vesicles loaded with 1 mM cold urate or with 5 mM lactate was, respectively: 0.7 and 0.3 μM for benzbromarone; 6 and 4 μM for salicylate; 133 and 13 μM for losartan; 520 and 190 μM for sulfinpyrazone and 807 and 150 μM, for probenecid. The IC50 ratio for [14C]-urate uptake in exchange for cold urate or for lactate varied from about 1 for salicylate to 10 for losartan, supporting the hypothesis that two distinct anion exchangers are involved in urate transport. Application of Hill equation revealed that urate/anion exchangers have more than one binding site, possibly two binding sites with high cooperativity, for benzbromarone and sulfinpyrazone, but only one for probenecid, salicylate and losartan. The uricosuric diuretic, tienilic acid was 10 to 50 times more potent than hydrochlorothiazide, chlorothiazide and furosemide, for inhibiting [14C]-urate uptake in exchange for cold urate. This higher potency is the reason of its uricosuric properties. All uricosuric agents, as well as the antiuricosuric agents, pyrazinoate and ethambutol, had a much lower potency for inhibiting [14C]-urate uptake through the voltage sensitive pathway (apical secretory step) than through the urate/anion exchangers. This suggests that antiuricosuria, induced by pyrazinoate and ethambutol, as well as by low concentrations of uricosuric agents, does not result from an inhibition of the apical voltage sensitive pathway.
Footnotes
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Send reprint requests to: Dr. Françdoise Roch-Ramel, Institut de Pharmacologie, Bugnon 27, CH 1005 Lausanne, Switzerland.
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↵1 This work was supported by the Swiss National Fund for Scientific Research Grant 32–43451.95.
- Abbreviations:
- BBMV
- brush-border membrane vesicles
- FEurate
- fractional excretion of urate
- IC50
- concentration of inhibitor which yielded 50% inhibition of urate uptake
- napp
- number of apparent binding sites calculated by Hill plot equation
- M1
- 1′-hydroxybenzbromarone
- M2
- 6-hydroxybenzbromarone
- Received July 23, 1996.
- Accepted October 7, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
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