Repaglinide (repaglinide)

Repaglinide, a meglitinide (glinide) derivative, is a short-acting, insulinotropic antidiabetic agent.

Repaglinide, a carbamoylmethyl benzoic acid derivative, is a short-acting, insulinotropic antidiabetic agent. As with sulfonylurea antidiabetic agents, functioning pancreatic beta-cells are required for repaglinide's hypoglycemic activity since the drug lowers blood glucose concentrations principally by augmenting endogenous insulin secretion from the pancreas in response to a meal. Studies in pancreatic islet-cell cultures indicate a glucose-dependent relationship for the insulinotropic action of repaglinide.

Unlike sulfonylurea antidiabetic agents, repaglinide does not stimulate insulin release in the absence of glucose, and insulin release is diminished at low glucose concentrations. As blood glucose concentrations increase, repaglinide augments the glucose-induced closure of ATP-sensitive potassium channels and, thereby, the release of insulin. However, repaglinide exerts most of its insulinotropic activity at intermediate glucose concentrations (54-180 mg/dL).

At high glucose concentrations (exceeding 270 mg/dL), addition of repaglinide does not augment the insulin release already stimulated by high extracellular glucose concentrations. The effect of repaglinide on potassium and calcium channels is somewhat selective for pancreatic beta-cells and does not appear to affect skeletal or cardiac muscle or thyroid tissue. Limited data in animals suggest that long-term administration of repaglinide may be associated with some improvement in beta-cell responsiveness (as determined by an increase in basal and glucose-stimulated insulin output); however, additional studies are required to confirm such an effect.

In patients previously treated with oral antidiabetic agents, body weight does not change during repaglinide therapy. In therapy-naive patients receiving repaglinide in clinical trials, body weight increased by 3.3%. Although the exact mechanisms associated with such alterations in weight have not been established, suggested mechanisms include an increase in insulin secretion (which may increase appetite), stimulation of lipogenesis in fat tissue, or resistance to the actions of leptin (which decreases appetite and increases energy expenditure).

Repaglinide is rapidly and completely absorbed from the GI tract following oral administration. Following single and multiple oral doses of repaglinide in healthy individuals or patients with type 2 diabetes mellitus, peak plasma drug concentrations are attained within approximately 1 hour. The absolute bioavailability of repaglinide averages approximately 56%.

Serum insulin concentrations begin to increase within 30 minutes following administration of repaglinide and reach a peak approximately 1.5 hours after a dose. Following acute oral administration of repaglinide in healthy individuals, the maximal glycemic effect occurs within 3-3.5 hours. Plasma insulin concentrations increase in proportion to dose with repaglinide and return toward premeal concentrations between meals and at bedtime.

In patients with type 2 diabetes mellitus, bioavailability (as determined by AUC) of repaglinide over the therapeutic dosage range (0.5-4 mg) was 15-70% higher in females than in males, although this difference disappeared when normalized for dosage and weight. In some studies, administration of repaglinide with food reduced the extent of GI absorption (as determined by AUC) by up to 12.4%; time to peak plasma concentration and mean peak plasma concentration were reduced by up to 30 and up to 20%, respectively. Administration of the drug with a high-fat meal reportedly reduced peak plasma concentration and AUC slightly but did not affect time to peak concentration.

The clinical importance of these effects has not been determined. Protein binding (e.g., to albumin and alpha1-acid glycoprotein) of repaglinide exceeds 98%. Studies in rats indicate that repaglinide is distributed into breast milk.

Repaglinide is rapidly metabolized by the cytochrome P-450 (CYP) microsomal isoenzymes 3A4 and 2C8, principally via oxidation and dealkylation to the major dicarboxylic acid derivative (M2) and by further oxidation to an aromatic amine derivative (M1). An acyl glucuronide metabolite (M7) is formed from the carboxylic acid group of repaglinide; a number of other unidentified metabolites also have been detected. The metabolites of repaglinide do not have clinically important hypoglycemic activity.

The elimination half-life of repaglinide is about 1 hour. Within 96 hours following oral administration of a dose of radiolabeled repaglinide, approximately 90% of the dose was excreted in feces (<2% as repaglinide) and 8% was excreted in urine (0.1% as repaglinide). The major metabolite, the dicarboxylic acid derivative, accounts for about 60% of the administered radiolabeled dose.

Renal impairment is associated with increases in plasma concentrations of repaglinide. Because plasma drug concentrations are highly variable in individuals with renal impairment, AUC for repaglinide does not correlate or correlates only weakly with creatinine clearance. In patients with type 2 diabetes mellitus receiving repaglinide, increases in peak plasma concentrations and AUC were noted in patients with severe renal impairment (creatinine clearance 20-40 mL/minute); such alterations in the pharmacokinetics of the drug were not found in patients with mild to moderate renal impairment.

In patients with hepatic impairment, elimination of unbound repaglinide is reduced, resulting in higher plasma concentrations of unbound and total repaglinide, higher AUC, and longer mean residence time compared with that in healthy individuals.

USES: Repaglinide is used alone or with other medications to control high blood sugar along with a proper diet and exercise program. It is used in people with type 2 diabetes. Controlling high blood sugar helps prevent kidney damage, blindness, nerve problems, loss of limbs, and sexual function problems.

Proper control of diabetes may also lessen your risk of a heart attack or stroke. It works by stimulating the body to produce more insulin. Insulin is a natural substance that allows the body to properly use sugar from the diet.

Generic name: repaglinide
Pronunciation: (reh-PAGG-lin-ide)

The following indications are listed for Repaglinide:

• Type 2 Diabetes Mellitus

Also known as: Adult Onset Diabetes, Adult Onset Diabetes Mellitus, Adult Onset Dm, Diabetes Mellitus Type 2, Diabetes Mellitus Type Ii, Ketosis-Resistant Diabetes Mellitus, Ketosis-Resistant Dm, Maturity Onset Diabetes, Maturity Onset Diabetes Mellitus, Non-Insulin Dependent Diabetes Mellitus, Non-Insulin-Dependent Diabetes Mellitus, Type Ii Diabetes Mellitus.

No ICD codes are available for this drug.