GLYNASE® PRESTAB® Clinical Pharmacology

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Glyburide appears to lower the 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 Type II diabetic patients, the blood glucose lowering effect persists despite a gradual decline in the insulin secretory response to the drug. Extrapancreatic effects may be involved in the mechanism of action of oral sulfonylurea hypoglycemic drugs. The combination of glyburide and metformin may have a synergistic effect, since both agents act to improve glucose tolerance by different but complementary mechanisms.

Some patients who are initially responsive to oral hypoglycemic drugs, including glyburide, may become unresponsive or poorly responsive over time. Alternatively, glyburide may be effective in some patients who have become unresponsive to one or more other sulfonylurea drugs.

In addition to its blood glucose lowering actions, glyburide produces a mild diuresis by enhancement of renal free water clearance. Disulfiram-like reactions have very rarely been reported in patients treated with glyburide.

Pharmacokinetics

Single dose studies with GLYNASE PresTab Tablets in normal subjects demonstrate significant absorption of glyburide within one hour, peak drug levels at about two to three hours, and low but detectable levels at twenty-four hours.

Bioavailability studies have demonstrated that GLYNASE PresTab Tablets 3 mg provide serum glyburide concentrations that are not bioequivalent to those from MICRONASE Tablets 5 mg. Therefore, the patient should be retitrated.

In a single-dose bioavailability study (see Figure A) in which subjects received GLYNASE PresTab Tablets 3 mg and MICRONASE Tablets 5 mg with breakfast, the peak of the mean serum glyburide concentration-time curve was 97.2 ng/mL for GLYNASE PresTab Tablets 3 mg and 87.5 ng/mL for MICRONASE Tablets 5 mg. The mean of the individual maximum serum concentration values of glyburide (Cmax) from GLYNASE PresTab Tablets 3 mg was 106 ng/mL and that from MICRONASE Tablets 5 mg was 104 ng/mL. The mean glyburide area under the serum concentration-time curve (AUC) for this study was 568 ng × hr/mL for GLYNASE PresTab Tablets 3 mg and 746 ng × hr/mL for MICRONASE Tablets 5 mg.

Mean serum levels of glyburide, as reflected by areas under the serum concentration-time curve, increase in proportion to corresponding increases in dose. Multiple dose studies with glyburide in diabetic patients demonstrate drug level concentration-time curves similar to single dose studies, indicating no buildup of drug in tissue depots.

In a steady-state study in diabetic patients receiving GLYNASE PresTab Tablets 6 mg once daily or GLYNASE PresTab Tablets 3 mg twice daily, no difference was seen between the two dosage regimens in average 24-hour glyburide concentrations following two weeks of dosing. The once-daily and twice-daily regimens provided equivalent glucose control as measured by fasting plasma glucose levels, 4-hour postprandial glucose AUC values, and 24-hour glucose AUC values. Insulin AUC response over the 24-hour period was not different for the two regimens. There were differences in insulin response between the regimens for the breakfast and supper 4-hour postprandial periods, but these did not translate into differences in glucose control.

The serum concentration of glyburide in normal subjects decreased with a half-life of about four hours.

In single dose studies in fasting normal subjects who were administered glyburide (MICRONASE Tablets) in doses ranging from 1.25 mg to 5 mg, the degree and duration of blood glucose lowering is proportional to the dose administered and to the area under the drug level concentration-time curve. The blood glucose lowering effect persists for 24 hours following single morning doses in nonfasting diabetic patients. Under conditions of repeated administration in diabetic patients, however, there is no reliable correlation between blood drug levels and fasting blood glucose levels. A one year study of diabetic patients treated with glyburide showed no reliable correlation between administered dose and serum drug level.

The major metabolite of glyburide is the 4-trans-hydroxy derivative. A second metabolite, the 3-cis-hydroxy derivative, also occurs. These metabolites probably contribute no significant hypoglycemic action in humans since they are only weakly active (1/400th and 1/40th as active, respectively, as glyburide) in rabbits.

Glyburide is excreted as metabolites in the bile and urine, approximately 50% by each route. This dual excretory pathway is qualitatively different from that of other sulfonylureas, which are excreted primarily in the urine.

Sulfonylurea drugs are extensively bound to serum proteins. Displacement from protein binding sites by other drugs may lead to enhanced hypoglycemic action. In vitro, the protein binding exhibited by glyburide is predominantly non-ionic, whereas that of other sulfonylureas (chlorpropamide, tolbutamide, tolazamide) is predominantly ionic. Acidic drugs such as phenylbutazone, warfarin, and salicylates displace the ionic-binding sulfonylureas from serum proteins to a far greater extent than the non-ionic binding glyburide. It has not been shown that this difference in protein binding will result in fewer drug-drug interactions with glyburide in clinical use.