The pharmacokinetics of glyburide (Gb) and its active metabolites, 4-trans-hydroxyglibenclamide (M1) and 3-cis-hydroxyglibenclamide (M2), were compared in eight healthy subjects. After an overnight fast, each subject received a 3.5-mg single dose of Gb, M1 or M2 intravenously in random cross-over order. For comparison, a 3.5-mg oral dose of micronized formulation of Gb was also given in a test. The subjects continued to fast until standard meals were given at 0.5 and 5.5 h after each dose. Serum samples and urine fractions were collected for 10 h. Serum concentrations of Gb, M1 and M2, and urine concentrations of M1 and M2 were determined by a selective and sensitive liquid chromatographic method. The two metabolites had very similar pharmacokinetic profiles, except for volume of distribution and renal clearance. Estimated mean volume of distribution, total and renal clearance of M1 and M2 were 20.8 +/- 8.4 litres, 11.9 +/- 1.7 litres/h, 13.5 +/- 3.7 litres/h and 15.5 +/- 5.5 litres, 10.4 +/- 1.3 litres/h, 8.6 +/- 1.6 litres/h, respectively. Estimates of the volume of distribution and total clearance were significantly higher than those of Gb, which were 7.44 +/- 1.53 litres, 4.42 +/- 0.56 litres/h intravenously and 9.32 +/- 2.79 litres, 4.09 +/- 0.45 litres/h orally. There was no significant difference in total metabolite urine recovery between intravenous or oral administration of Gb, suggesting almost complete oral bioavailability of the micronized glibenclamide formulation.