indication

For the treatment of non-insulin dependent-diabetes mellitus in conjunction with diet and exercise.

pharmacology

Insulin secretion by pancreatic β cells is partly controlled by cellular membrane potential. Membrane potential is regulated through an inverse relationship between the activity of cell membrane ATP-sensitive potassium channels (ABCC8) and extracellular glucose concentrations. Extracellular glucose enters the cell via GLUT2 (SLC2A2) transporters. Once inside the cell, glucose is metabolized to produce ATP. High concentrations of ATP inhibit ATP-sensitive potassium channels causing membrane depolarization. When extracellular glucose concentrations are low, ATP-sensitive potassium channels open causing membrane repolarization. High glucose concentrations cause ATP-sensitive potassium channels to close resulting in membrane depolarization and opening of L-type calcium channels. The influx of calcium ions stimulates calcium-dependent exocytosis of insulin granules. Repaglinide increases insulin release by inhibiting ATP-sensitive potassium channels in a glucose-dependent manner.

mechanism of action

Repaglinide activity is dependent on the presence functioning β cells and glucose. In contrast to sulfonylurea insulin secretatogogues, repaglinide has no effect on insulin release in the absence of glucose. Rather, it potentiates the effect of extracellular glucose on ATP-sensitive potassium channel and has little effect on insulin levels between meals and overnight. As such, repaglinide is more effective at reducing postprandial blood glucose levels than fasting blood glucose levels and requires a longer duration of therapy (approximately one month) before decreases in fasting blood glucose are observed. The insulinotropic effects of repaglinide are highest at intermediate glucose levels (3 to 10 mmol/L) and it does not increase insulin release already stimulated by high glucose concentrations (greater than 15 mmol/L). Repaglinide appears to be selective for pancreatic β cells and does not appear to affect skeletal or cardiac muscle or thyroid tissue.

toxicity

LD₅₀ >1 g/kg (rat) (W. Grell)

biotransformation

Repaglinide is rapidly metabolized via oxidation and dealkylation by cytochrome P450 3A4 and 2C9 to form the major dicarboxylic acid derivative (M2). Further oxidation produces the aromatic amine derivative (M1). Glucuronidation of the carboxylic acid group of repaglinide yields an acyl glucuronide (M7). Several other unidentified metabolites have been detected. Repaglinide metabolites to not possess appreciable hypoglycemic activity.

absorption

Rapidly and completely absorbed following oral administration. Peak plasma concentrations are observed within 1 hour (range 0.5-1.4 hours). Absolutely bioavailability is approximately 56%. Maximal biological effect is observed within 3-3.5 hours and plasma insulin levels remain elevated for 4-6 hours

half life

1 hour

route of elimination

90% eliminated in feces (<2% as unchanged drug), 8% in urine (0.1% as unchanged drug)

drug interactions

Acebutolol: Acebutolol may decrease symptoms of hypoglycemia and increase the time required for the body to compensate for hypoglycemia.

Atenolol: The beta-blocker, atenolol, may decrease symptoms of hypoglycemia.

Betaxolol: The beta-blocker, betaxolol, may decrease symptoms of hypoglycemia.

Bevantolol: The beta-blocker, bevantolol, may decrease symptoms of hypoglycemia.

Bisoprolol: The beta-blocker, bisoprolol, may decrease symptoms of hypoglycemia.

Carteolol: The beta-blocker, carteolol, may decrease symptoms of hypoglycemia.

Carvedilol: The beta-blocker, carvedilol, may decrease symptoms of hypoglycemia.

Clarithromycin: Clarithromycin may increase the effect of repaglinide.

Cyclosporine: Cyclosporine may increase the therapeutic and adverse effects of repaglinide.

Erythromycin: The macrolide, erythromycin, may increase the effect of repaglinide.

Esmolol: The beta-blocker, esmolol, may decrease symptoms of hypoglycemia.

Gemfibrozil: Gemfibrozil may increase the effect and toxicity of repaglinide.

Glucosamine: Possible hyperglycemia

Josamycin: The macrolide, josamycin, may increase the effect of repaglinide.

Labetalol: The beta-blocker, labetalol, may decrease symptoms of hypoglycemia.

Metoprolol: The beta-blocker, metoprolol, may decrease symptoms of hypoglycemia.

Nadolol: The beta-blocker, nadolol, may decrease symptoms of hypoglycemia.

Oxprenolol: The beta-blocker, oxprenolol, may decrease symptoms of hypoglycemia.

Penbutolol: The beta-blocker, penbutolol, may decrease symptoms of hypoglycemia.

Pindolol: The beta-blocker, pindolol, may decrease symptoms of hypoglycemia.

Practolol: The beta-blocker, practolol, may decrease symptoms of hypoglycemia.

Propranolol: The beta-blocker, propranolol, may decrease symptoms of hypoglycemia.

Rifampin: Rifampin decreases the effect of repaglinide

Sotalol: The beta-blocker, sotalol, may decrease symptoms of hypoglycemia.

Telithromycin: Telithromycin may reduce clearance of Repaglinide. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Repaglinide if Telithromycin is initiated, discontinued or dose changed.

Timolol: The beta-blocker, timolol, may decrease symptoms of hypoglycemia.

Voriconazole: Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of repaglinide by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of repaglinide if voriconazole is initiated, discontinued or dose changed.