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Pharmacology: Glipizide appears to lower blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning β-cells in the pancreatic islets. Stimulation of insulin secretion by glipizide in response to a meal is of major importance. The insulinotropic response to a meal is enhanced with Glucotrol XL administration in diabetic patients. The postprandial insulin and C-peptide responses continue to be enhanced after at least 6 months of treatment. Reductions in HbA1C and fasting plasma glucose were similar in younger and older patients.
Other Effects: One study has shown that glipizide GITS therapy is effective in controlling blood glucose without deleterious effects on the plasma lipoprotein profiles of patients treated for type 2 diabetes. Those changes were well correlated with the reduction achieved in fasting glucose levels.
Pharmacokinetics: Beginning 2-3 hrs after administration of Glucotrol XL, plasma drug concentrations gradually rise reaching maximum concentrations within 6-12 hrs after dosing. With subsequent once-daily dosing of Glucotrol XL, effective plasma glipizide concentrations are maintained throughout the 24-hr dosing interval with less peak to trough fluctuation than that observed with twice-daily dosing of immediate-release glipizide.
The mean relative bioavailability of glipizide in 21 males with type 2 diabetes after administration of Glucotrol XL 20 mg, compared to immediate-release glipizide (10 mg given twice daily) was 81 ± 22% at steady state.
Steady-state plasma concentrations were achieved by at least the 5th day of dosing with Glucotrol XL. Approximately 1-2 days longer were required to reach steady state in patients >65 years. No accumulation of drug was observed in patients with type 2 diabetes during chronic dosing with Glucotrol XL. Administration of Glucotrol XL with food has no effect on the 2-3 hrs lag time in drug absorption. In a single dose, food effect study, the administration of Glucotrol XL immediately before a high-fat breakfast resulted in a 40% increase in the glipizide mean Cmax value, which was significant, but the effect on the AUC was not significant. There was no change in glucose response between the fed and fasting state. Markedly reduced GI retention times of Glucotrol XL over prolonged periods (eg, short bowel syndrome) may influence the pharmacokinetic profile of the drug and potentially result in lower plasma concentrations.
In a multiple-dose study in 26 males with type 2 diabetes, the pharmacokinetics of glipizide were linear over the dose range of Glucotrol XL 5-60 mg in that the plasma drug concentrations increased proportionately with dose. In a single-dose study in 24 healthy subjects, four 5-mg, two 10-mg and one 20-mg Glucotrol XL tablets were bioequivalent.
Glipizide is eliminated primarily by hepatic biotransformation: Less than 10% of a dose is excreted as unchanged drug in urine and feces; approximately 90% of a dose is excreted as biotransformation products in urine (80%) and feces (10%). Glipizide is 98-99% bound to serum proteins, primarily to albumin.
Toxicology: Preclinical Safety Data: In nonclinical studies, the acute oral toxicity of glipizide was extremely low in all species tested (LD50 >4 g/kg). Acute toxicity studies showed no specific susceptibility. Chronic toxicity tests in rats and dogs at doses up to 8 mg/kg did not show any evidence of toxic effects.
A 20-month study in rats and an 18-month study in mice at doses up to 75 times the maximum human dose revealed no evidence of drug-related carcinogenicity. Bacterial and in vivo mutagenicity tests were uniformly negative. Studies in rats of both sexes at doses up to 75 times the human dose showed no effects on fertility.
