Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: Generics [UK] Ltd t/a Mylan, Station Close, Potters Bar, Hertfordshire, EN6 1TL
Pharmacotherapeutic group: Drugs used in diabetes, blood glucose lowering drugs excl. insulins, sulfonylureas
ATC code: A10BB07
Glipizide is an oral blood-glucose-lowering drug of the sulfonylurea class. The primary mode of action of glipizide is the stimulation of insulin secretion from the beta-cells of pancreatic islet tissue. Stimulation of insulin secretion by glipizide in response to a meal is of major importance. Fasting insulin levels are not elevated even on long-term glipizide administration, but the post-prandial insulin response continues to be enhanced after at least 6 months of treatment. The insulinotropic response to a meal occurs within 30 minutes after oral dose of glipizide in diabetic patients, but elevated insulin levels do not persist beyond the time of the meal challenge. There is also increasing evidence that extrapancreatic effects involving potentiation of insulin action form a significant component of the activity of glipizide.
Blood sugar control persists for up to 24 hours after a single dose of glipizide, even though plasma levels have declined to a small fraction of peak levels by that time (see section 5.2).
Gastrointestinal absorption of glipizide in humans is uniform, rapid and essentially complete. Peak plasma concentrations occur 1 to 3 hours after a single oral dose. The half-life of elimination ranges from 2 to 4 hours in normal subjects, whether given intravenously or orally. The metabolic and excretory patterns are similar with the two routes of administration, indicating that first-pass metabolism is not significant. Glipizide does not accumulate in plasma on repeated oral administration. Total absorption and disposition of an oral dose were unaffected by food in normal volunteers, but absorption was delayed by about 40 minutes. Thus, glipizide was more effective when administered about 30 minutes before, rather than with, a test meal in diabetic patients.
Protein binding was studied in serum from volunteers who received either oral or intravenous glipizide and found to be 98% to 99% one hour after either route of administration. The apparent volume of distribution of glipizide after intravenous administration was 11 L, indicative of localisation within the extracellular fluid compartment. In mice, no glipizide or metabolites were detectable autoradiographically in the brain or spinal cord of males or females, nor in the foetuses of pregnant females. In another study, however, very small amounts of radioactivity were detected in the foetuses of rats given labelled drug.
The metabolism of glipizide is extensive and occurs mainly in the liver.
The primary metabolites are inactive hydroxylation products and polar conjugates and are excreted mainly in the urine. Less than 10% unchanged glipizide is found in urine.
Acute toxicity studies showed no specific susceptibility. The acute oral toxicity of glipizide was extremely low in all species tested (LD50 greater than 4 g/kg). Chronic toxicity tests in rats and dogs at doses up to 8.0 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 maximum human dose showed no effects on fertility.
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