Glucovance

[Glyburide/Metformin]

Clinical Pharmacology
CLINICAL PHARMACOLOGY

Mechanism of Action

GLUCOVANCE combines metformin hydrochloride and glyburide, two antihyperglycemic agents with complementary mechanisms of action, to improve glycemic control in patients with type 2 diabetes. Glyburide appears to lower blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which glyburide lowers blood glucose during long-term administration has not been clearly established.

With chronic administration in patients with type 2 diabetes, the blood glucose lowering effects persists despite a gradual decline in the insulin secretory response to the drug. Extra-pancreatic effects may be involved in the mechanism of action of oral sulfonylurea hypoglycemic drugs. Metformin hydrochloride is an antihyperglycemic agent that improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin hydrochlo-ride decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.

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Pharmacokinetics

Absorption and Bioavailability

GLUCOVANCE

In bioavailability studies of GLUCOVANCE 2.5 mg/ 500 mg and 5 mg/ 500 mg, the mean area under the plasma concentration time curve (AUC) for the glyburide component was 18% and 7%, respec-tively, greater than that of the Micronase ® brand of glyburide coadministered with metformin. The glyburide component of GLUCOVANCE, therefore, is not bioequivalent to Micronase ® .

The met-formin component of GLUCOVANCE is bioequivalent to metformin coadministered with glyburide. Following administration of a single GLUCOVANCE 5 mg/ 500 mg tablet, with either a 20% glucose solution or a 20% glucose solution with food, there was no effect of food on the C max and a relatively small effect of food on the AUC of the glyburide component. The T max for the glyburide component was shortened from 7.5 hours to 2.75 hours with food compared to the same tablet strength admin-istered fasting with a 20% glucose solution. The clinical significance of an earlier T max for glyburide after food is not known. The effect of food on the pharmacokinetics of the metformin component was indeterminate.

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