It has been proposed that a urate-anion exchanger system in brush border membrane vesicles (BBMV), which mediates hydroxyl ion (OH-) gradient-dependent urate uptake, is the most likely route for the mediation of urate transport in the first step of urate reabsorption in the proximal tubules. Luminal drugs which inhibit urate reabsorption would inhibit the transport of urate into the cell by blocking the urate-anion exchanger. To confirm this hypothesis, we investigated the inhibitory effects of well-known uricosuric drugs on the OH-/urate exchange in BBMV. The rank order of potency was benzbromarone greater than tienilic acid greater than sulfinpyrazone greater than probenecid, which is consistent with clinical doses in man. AA-193 (5-chloro-7,8-dihydro-3-phenylfuro[2,3-g]-1,2-benzisoxazole-7-carb oxylic acid), an excellent candidate for a uricosuric, exerted the most potent inhibition on urate uptake (Ki = 0.12 microM). In contrast with that by stilbene disulfonates, the inhibition by AA-193 or benzbromarone was reversible.