Amaramet Mechanism of Action

Pharmacological Properties: metformin and sulfonamides; Belongs to the class of combinations of oral blood glucose lowering drugs. ATC Classification: A10BD02.
Pharmacology: Glimepiride and Metformin hydrochloride contains two oral anti-hyperglycemic drugs used in the management of type-2 diabetes mellitus - Non-insulin dependent diabetes mellitus (NIDDM).
Glimepiride: Glimepiride reduces blood glucose levels by correcting both defective insulin secretion and peripheral insulin resistance. It interacts with specific receptors at the plasma membrane of the insulin releasing pancreatic β-cells where they inhibit ATP-sensitive K+ channels resulting in depolarization of the cell membrane, opening of voltage sensitive Ca+ channels, increase in intracellular calcium levels and subsequent insulin release.
Metformin: Metformin acts as an antihyperglycemic agent by improving hepatic and peripheral tissue sensitivity to insulin. It also appears to have beneficial effect on serum lipid levels and so on fibrinolytic activity. Metformin therapy is not associated with increase in body weight. Metformin decreases glucose production, decreases levels and so on fibrinolytic activity. Metformin therapy is not associated with increase in body weight. Metformin decreases glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
Rationality for Combination of Glimepiride and Metformin: Sulfonylureas and biguanides act complementary to each other. Both compounds have an additive antihyperglycemic effect without increasing the adverse effects of either pharmacological class.
Glimepiride acts via stimulating b-cells of pancreas to release insulin and also increases peripheral sensitivity of insulin. Metformin acts via enhanced peripheral glucose uptake and utilization. It also reduces hepatic glucose production, thereby metformin diminishes insulin resistance.
There are reports in which combination treatment of sulfonylureas with metformin has been reported to achieve satisfactory glycemic control for several years. The combination may therefore provide additional glycemic control (blood glucose lowering effect by 20%).
Glimepiride has less propensity to cause hypoglycaemia and increase in body weight as compared to other sulfonylureas. Since metformin is reported to have predominant peripheral mechanism of action, therefore it lacks the anabolic effects of sulfonylureas and does not cause weight gain.
Metformin is associated with a decrease in fasting and postprandial plasma insulin and triglyceride levels, increase in HDL-cholesterol, increase of tissue plasminogen activator, decrease in platelet aggregation.
Pharmacokinetically the two drugs appear to be compatible, as metformin is not plasma protein bound and does not get metabolized in liver. So interaction with glimepiride (having 99% plasma protein binding and metabolized via liver) does not appear to be possible. Hence, the combination of glimepiride and metformin would help in treatment of Non-Insulin Dependent Diabetes Mellitus (NIDDM).
Pharmacokinetics: Absorption: Glimepiride: After oral administration glimepiride is completely absorbed from the GI tract. Studies have shown significant absorption of glimepiride within 1 hour after administration and peak drug levels (Cmax) at 2 to 3 hours. When glimepiride was given with meals, the mean Tmax (time to reach Cmax) was slightly increased (12%) and the mean Cmax and AUC (area under the curve) were slightly decreased (8% and 9%, respectively).
Metformin sustained-release: The absolute bioavailability of a metformin 500 mg tablet given under fasting conditions is approximately 50-60%. Following a single oral dose of metformin sustained-release, Cmax is achieved within 4-8 hours. Peak plasma levels are approximately 20% lower compared to the same dose of metformin immediate release, however the extent of absorption (as measured by AUC) is similar to immediate release. Both high and low fat meals had the same effect on the pharmacokinetics of sustained-release.
Distribution: Glimepiride: After intravenous dosing in normal subjects, the volume of distribution (Vd) was 8.8 L (113 mL/kg). Protein binding was greater than 99.5%.
Metformin sustained-release: Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time. Distribution studies with metformin sustained-release have not been conducted. At usual clinical doses and dosing schedules of immediate-release metformin, steady state plasma concentrations of metformin are reached within 24-48 hours and are generally <1 μg/mL. During controlled clinical trials of immediate-release metformin, maximum metformin plasma levels did not exceed 5 μg/mL, even at maximum doses.
Metabolism: Glimepiride: Glimepiride is completely metabolized by oxidative biotransformation. The major metabolites are the cyclohexyl hydroxyl methyl derivative (M1) and the carboxyl derivative (M2). Cytochrome P450 II C9 has been shown to be involved in the biotransformation of glimepiride to M1. M1 is further metabolized to M2 by one or several cytosolic enzymes. M1, but not M2, possesses about ¹/₃ of the pharmacological activity as compared to its parent; however, whether the glucose-lowering effect of M1 is clinically significant is not clear.
Metformin sustained-release: Metabolism studies with metformin sustained-release have not been conducted. However, intravenous single-dose studies in normal subjects demonstrate that metformin immediate release does not undergo hepatic metabolism or biliary excretion.
Excretion: Glimepiride: When 14C-glimepiride was given orally, approximately 60% of the total radioactivity was recovered in the urine in 7 days and M1 (predominant) and M2 accounted for 80-90% of that of the recovered in the urine. Approximately 40% of the total radioactivity was recovered in feces and M1 and M2 (predominant) accounted for about 70% of that recovered in feces. No parent drug was recovered from urine or feces.
Metformin: Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism or biliary excretion. Renal clearance of metformin is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.