Diabemin XR Mechanism of Action

Pharmacology: Pharmacodynamics: Metformin is a biguanide oral antihyperglycemic agent, which lowering both basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycemia. Metformin may act via 3 mechanisms: (1) in the liver, reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis; (2) in muscle, by increasing insulin sensitivity, improving peripheral glucose uptake and utilization and (3) delay of intestinal glucose absorption.
Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase. Metformin increases the transport capacity of all types of membrane glucose transporters (GLUT).
Metformin is associated with either a stable body weight or modest weight loss. In humans, independently of its action on glycemia, metformin has favorable effects on lipid metabolism. Metformin reduces total cholesterol, LDL cholesterol and triglyceride levels.
Pharmacokinetics: Metformin hydrochloride extended-release tablet comprise of a dual hydrophilic polymer matrix system. Metformin hydrochloride is combined with a drug release controlling polymer to form an "inner" phase, which is then incorporated as discrete particles into an "external" phase of a second polymer. After administration, fluid from the gastrointestinal tract enters the extended-release tablet, causing the polymers to hydrate and swell. The drug is released slowly from the dosage form by a process of diffusion through the gel matrix that is essentially independent of pH. The hydrated polymer system is not rigid and is expected to be broken up by normal peristalsis in the GI tract. The biologically inert components of the extended-release tablet may occasionally remain intact during GI transit and will be eliminated in the feces.
Absorption: Metformin hydrochloride (DIABEMIN XR) bioequivalence study was conducted by combining single and multiple doses in the administration condition. The single dose condition was performed under fasting conditions, while, the multiple doses condition was performed with normal diabetic meals. Following the single dose condition, C_max is achieved with a median value of 3.5 hours and a range of 1.5 to 4.5 hours, while AUC_t, AUC_inf and C_max are similar to the reference drug. Following the multiple doses condition, AUC_tau, C_max and C_min are similar to the reference drug.
The composition of the meal does not influence the absorption. After repeated administration of up to a dose of 2 g of metformin, metformin does not accumulate in the plasma.
Distribution: Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak is lower than the plasma peak and appears at approximately the same time. The red blood cells most likely represent a secondary compartment of distribution.
Metabolism: Metformin does not undergo metabolism and it is excreted unchanged in the urine. No metabolites have been identified in humans. There is no biliary elimination.
Elimination: Renal clearance of metformin is >400 mL/minute, indicating that metformin is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 hours.
The fast elimination of metformin in patients with normal renal function shows no accumulation of metformin in the body at the recommended dosage.
When renal function is impaired, renal clearance is decreased in proportion to that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of metformin in plasma.