OBJECTIVE To assess the hypoglycemie effect and the insulin-releasing effect of the main glyburide (glibenclamide) metabolites 4-trans-hydroxy-glibenclamide (Ml) and 3-cis-hydroxy-glibenclamide (M2) in humans.

RESEARCH DESIGN AND METHODS Eight healthy subjects participated in a placebo-controlled, randomized, single-blind crossover study with five single-dose tests, 3 months apart: 3.5 mg glibenclamide (Gb) orally, 3.5 mg Gb intravenously, 3.5 mg Ml intravenously, 3.5 mg M2 intravenously, and placebo intravenously, each in the fasting state. Standardized meals were given 0.5 and 5.5 h after each medication. Blood glucose levels were measured by a glucose oxidase method, and serum insulin concentrations were analyzed by a specific immunoassay.

RESULTS Blood glucose levels during the first 5 h were significantly lowered not only by Gb but also by Ml and M2. The mean ± SE blood glucose reductions (versus placebo) expressed as percent of area under the curve (AUC) (0-5 h) were 18.2 ± 3.3% for Ml, 12.5 ± 2.3% forM2,19.9 ± 2.1% for intravenous Gb, and 23.8 ± 1.2% for Gb orally. Serum insulin levels were significantly increased by Gb as well as by Ml and M2.

CONCLUSIONS The two main metabolites of glyburide (glibenclamide) have a hypoglycémie effect in humans, which is due to increased insulin secretion.