COMPARISON OF THE KINETICS OF GLYBURIDE AND ITS ACTIVE METABOLITES INHUMANS

The pharmacokinetics of glyburide (Gb) and its active metabolites, 4-t rans-hydroxyglibenclamide (M1) and 3-cis-hydroxyglibenclamide (M2), we re compared in eight healthy subjects. After an overnight fast, each s ubject 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 microni zed 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 d ose. 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 m ethod. 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, respec tively. Estimates of the volume of distribution and total clearance we re significantly higher than those of Gb, which were 7.44 +/- 1.53 lit res, 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 to tal metabolite urine recovery between intravenous or oral administrati on of Gb, suggesting almost complete oral bioavailability of the micro nized glibenclamide formulation.