Glubitor/Glubitor-OD Mechanism of Action

Pharmacotherapeutic group: Glubitor: Drugs used in diabetes, blood glucose lowering drugs, excl. insulins, sulfonylureas. Glubitor-OD: PR tab: Sulfonamides, urea derivatives. ATC code: Glubitor: A10BB09.
Pharmacology: Pharmacodynamics: Glubitor/Glubitor-OD (PR tab): Mechanism of action: Gliclazide is a hypoglycemic sulfonylurea oral antidiabetic active substance differing from other related compounds by an N-containing heterocyclic ring with an endocyclic bond.
Gliclazide reduces blood glucose levels by stimulating insulin secretion from the β-cells of the islets of Langerhans. Increase in postprandial insulin and C-peptide secretion persists after two years of treatment.
In addition to these metabolic properties, gliclazide has hemovascular properties.
Pharmacodynamic effects: Effects on insulin release: In type 2 diabetics, gliclazide restores the first peak of insulin secretion in response to glucose and increases the second phase of insulin secretion. A significant increase in insulin response is seen in response to stimulation induced by a meal or glucose.
Hemovascular properties: Gliclazide decreases microthrombosis by two mechanisms, which may be involved in complications of diabetes: a partial inhibition of platelet aggregation and adhesion, with a decrease in the markers of platelet activation (beta thromboglobulin, thromboxane B₂); an action on the vascular endothelium fibrinolytic activity with an increase in tPA activity.
Glubitor-OD (MR tab): Gliclazide is a sulfonylurea oral antidiabetic agent whose primary action is to increase the sensitivity of the β-cells from the pancreas. It potentiates glucose-stimulated insulin secretion from functioning pancreatic islet β-cells inhibiting ATP-sensitive potassium (K⁺-ATP) channels resulting in depolarization which opens voltage-sensitive calcium channels and brings about influx of calcium that triggers insulin release.
As with other sulfonylureas, gliclazide has actions on peripheral tissues. Gliclazide enhances glycogen synthesis and inhibits glycogenolysis and gluconeogenesis in the liver. Gliclazide may also improve peripheral glucose uptake in muscles.
Pharmacokinetics: Glubitor/Glubitor-OD (PR tab): Absorption: Plasma levels increase progressively during the first 6 hours, reaching a plateau, which is maintained from the sixth to the twelfth hour after administration. Intra-individual variability is low. Gliclazide is completely absorbed. Food intake does not affect the rate or degree of absorption.
Distribution: Plasma protein binding is approximately 95%. The volume of distribution is around 30 liters (L). A single daily intake maintains effective gliclazide plasma concentrations over 24 hours.
Biotransformation: Gliclazide is mainly metabolized in the liver and excreted in the urine; less than 1% of the unchanged form is found in the urine. No active metabolites have been detected in plasma.
Elimination: The elimination half-life of gliclazide varies/is between 12 and 20 hours.
Linearity/Non-Linearity: The relationship between the dose administered ranging up to 120 mg and the area under the concentration-time curve is linear.
Special populations: Elderly people: No clinically significant/relevant changes in the pharmacokinetic parameters have been observed in elderly patients.
Glubitor-OD (MR tab): Gliclazide is readily absorbed from the gastrointestinal tract although systemic bioavailability of an oral dose may vary considerably depending more on first-pass metabolism than absorption.
After an 80 mg dose of the immediate release preparation in normal volunteers, the average time to reach peak plasma concentration is about 4-6 hours. Gliclazide is about 95% bound to plasma proteins, mostly to albumin. Its volume of distribution is low. It has a mean plasma half-life of about 10-12 hours.
Gliclazide modified-release (Gliclazide OD) is a once-daily gliclazide formulation. The progressive release of gliclazide in this formulation parallels the 24-hour glycemic profile in untreated patients with type 2 diabetes. Gliclazide OD is highly bioavailable and its absorption is unaffected by food intake.
The following are important pharmacokinetic parameters of Gliclazide OD in adult volunteers who received 60 mg (2 tablets) single oral dose: See Table 1.

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Gliclazide OD's apparent clearance in type 2 diabetic patients is 0.9 L/h and its apparent volume of distribution is 19 L; the effective half-life is approximately 16 hours.
Gliclazide is distributed to the extracellular fluid, with high concentrations found in the liver, kidneys, skin, lungs, skeletal muscle, intestinal and cardiac tissue in animals. Gliclazide has been also shown to cross the placental barrier and penetrate the fetus.
Gliclazide is extensively metabolized with about <1% excreted in the urine unchanged. Approximately 60-70% of the administered dose appears to be excreted in the urine and 10-20% excreted in the feces.
The metabolism and excretion of sulfonylureas such as gliclazide may be slowed in patients with impaired renal and hepatic function.
Toxicology: Glubitor: Preclinical Safety Data: Preclinical data reveal no special hazards for humans based on conventional studies of repeated dose toxicity and genotoxicity. Long term carcinogenicity studies have not been done. No teratogenic changes have been shown in animal studies, but lower fetal body weight was observed in animals receiving doses 25 fold higher than the maximum recommended dose in humans.