The effects of different doses of sodium bicarbonate on the absorption and activity of non-micronized glibenclamide were studied in six healthy volunteers, using a randomized crossover design with four phases. The subjects ingested a single dose of non-micronized glibenclamide (2.5 mg) with 150 ml of water or with 150 ml of water containing 0.3, 1.0 or 3.0 g of sodium bicarbonate. Plasma concentrations of glibenclamide, insulin and glucose were measured. Coadministration of 1.0 or 3.0 g of sodium bicarbonate with non-micronized glibenclamide increased the area under the plasma glibenclamide concentration-time curve (AUC) from 0 to 1 h 30-fold (p < 0.05) and 38-fold (p < 0.05), respectively. The 1.0- and 3.0-g doses of sodium bicarbonate also increased the AUC of plasma glibenclamide from 0 to 2 h, about 3-fold (p = 0.05 and 0.07, respectively). The peak plasma concentration, peak time and total extent of absorption of glibenclamide and the insulin and glucose responses were not significantly altered by any of the doses of sodium bicarbonate studied. Concomitant ingestion of 1.0 or 3.0 g of sodium bicarbonate and non-micronized glibenclamide greatly increased the early bioavailability of glibenclamide. However, this interaction did not alter the activity of glibenclamide.