Glibenclamide Other names: Glyburide

Sulphonylureas act on pancreatic beta-cells by inhibiting ATP-sensitive potassium channels. The mechanisms of action proposed for this effect include stimulation of insulin release by beta-cells of the pancreas.

The minimum active concentration for the effect is considered to be 30-50 ng/mL glibenclamide.

Glibenclamide, a second-generation, short half-life sulphonylurea, is a hypoglycaemic agent that reduces blood-glucose by stimulating insulin release by the pancreas; this effect depends on the presence of active beta-cells or beta-cells made active by glibenclamide in the pancreatic islets in certain cases of neonatal diabetes.

Stimulation of insulin secretion by glibenclamide in response to a meal is of major significance. Administering glibenclamide to a diabetic enhances the post-prandial insulinotropic response. Post-prandial responses involving secretion of insulin and peptide-C continue to be enhanced after at least 6 months of treatment and even over many years in the case of neonatal diabetes by potassium channel disorders.

Glibenclamide has been shown to be effective in patients with mutations in the genes coding for the β-cell ATP-sensitive potassium channel and chromosome 6q24-related transient neonatal diabetes mellitus.

Absorption

After oral administration, glibenclamide is absorbed rapidly and induces its effect within 2.5 hours with a duration of up to 15 hours, although the elimination half-life is 5 to 10 hours. The food effect on the speed or the level of absorption of glibenclamide oral suspension has not been investigated.

Bioavailability studies have demonstrated that nonmicronised tablets provide serum glibenclamide concentrations that are not bioequivalent to those from micronised tablets.

Head to head comparative pharmacokinetic data following the application of glibenclamide suspension and micronised tablets are not available. The conversion rate between micronised tablets and the suspension has not been established.

A comparative study of relative bioavailability between two suspensions of glibenclamide oral suspensions (0.6 mg/mL and 6 mg/mL) and crushed glibenclamide tablets (5 mg) showed that when glibenclamide oral suspensions were administered, peak plasma concentrations of glibenclamide are reached 0.5 hours earlier than that observed with the crushed glibenclamide tablet (median value after administration is 2.5 hours compared to 3 hours). The values for maximum plasma concentrations (C_max) were similar for the two suspensions (201.71 ± 71.43 ng/mL for the 6 mg/mL suspension and 206.93 ± 67.33 ng/mL for the 0.6 mg/mL suspension). These values were approx. 40% greater than those obtained for the crushed tablet (148.34 ± 46.74 ng/mL).

The exposures were respectively similar for the two glibenclamide oral suspensions, and greater than those observed after administration of crushed glibenclamide tablets. The relative bioavailability was 121.6% for the 0.6 mg/mL suspension and 114.1% for the 6 mg/mL suspension compared to the crushed glibenclamide tablets.

Population pharmacokinetic approach was used to compare steady state concentrations following 0.9 mg twice daily in children with body weights between 10–30 kg and 1.25 mg twice daily in adults. The plasma glibenclamide levels in the simulated paediatric population were approximately 30%-60% lower than the adult levels. With smaller bodyweight the concentration increased but exceeded the adult plasma levels in minimal extents only for poor metabolizers. Distribution

Glibenclamide is strongly bound to plasma albumin (99%), which may account for certain drug interactions, but is not easily detached by acidic medicinal products.

Biotransformation and elimination

Glibenclamide is completely metabolised by the liver into 3 inactive metabolites excreted via bile (60%) and urine (40%); elimination is complete in 45 to 72 hours. Clinical studies appear to suggest that CYP2C9 contributes significantly to glibenclamide metabolism in vivo.

Liver failure reduces the metabolism of glibenclamide and therefore significantly slows down its elimination.

Biliary excretion of the metabolites increases in the event of kidney failure, proportionally to the severity of the change in renal function. Kidney failure does not affect its elimination as long as creatinine clearance remains above 30 ml/min.

The elimination half-lives were similar for the two suspensions (almost 8 hours) and a little shorter than those observed with the crushed glibenclamide tablets.

In repeated dose toxicity studies with oral administration of high doses of glibenclamide, effects on pancreatic beta-cells were observed (enlargement of the islets of Langerhans with irregularly configured islets and reduction in pancreatic β-cell granulation in rats at doses of ≥30 mg/kg/day, beta-cell exhaustion as indicated by depletion of insulin-containing granules in rabbits at doses of ≥100 mg/kg/day).