Metfor XR Mechanism of Action

Oral Anti-Diabetics.
A10BA02: Gastrointestinal tract and metabolism.
Pharmacology: Pharmacodynamics: Metformin is a biguanide with antihyperglycemic effects, lowering both basal and postprandial plasma glucose. It does not cause insulin secretion and therefore does not produce hypoglycemia.
Mechanism of action: Metformin may act via 3 mechanisms: reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis; in muscle, by increasing insulin sensitivity, improving peripheral glucose uptake and utilization; and 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).
Pharmacodynamic effects: In clinical studies, the major non glycemic effect of metformin is either weight stability or modest weight loss.
500 mg: In humans, independently of its action on glycaemia, immediate release metformin has favorable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term clinical studies: immediate release metformin reduces total cholesterol, LDL cholesterol and triglyceride levels. A similar action has not been demonstrated with the extended release formulation, possibly due to the evening administration, and an increase in triglycerides may occur.
Effects on body weight: 750 mg: In contrast to other commonly used antihyperglycemic agents, such as sulphonylureas or thiazolidinediones, treatment with metformin offers a considerable benefit for patients with type 2 diabetes by not causing an increase in body weight. By maintaining or reducing body weight, metformin limits other risk factors associated with increased weight. Over the long term this translates into more stable glycemic control and a decreased risk of diabetes complications.
Pharmacokinetics: Absorption: Meal composition has essentially little effect on metformin absorption from the sustained release formulation. After repeated delivery of up to 2000 mg of metformin as extended release tablets, no accumulation is detected.
500 mg: After an oral dose of the extended release tablet, metformin absorption is significantly delayed compared to the immediate release tablet with a Tmax at 7 hours (Tmax for the immediate release tablet is 2.5 hours).
At steady state, similar to the immediate release formulation, Cmax and AUC are not proportionally increased to the administered dose. The AUC after a single oral administration of 2000 mg of metformin extended release tablets is similar to that observed after administration of 1000 mg of metformin immediate release tablets b.i.d.
Intrasubject variability of Cmax and AUC of metformin extended release is comparable to that observed with metformin immediate release tablets.
During fasting conditions, there is a reduction of 30% in AUC (both in Cmax and Tmax are unaffected) when the extended release tablet is administered.
A mean peak plasma concentration of 1193 ng/mL is attained after a single oral dosage of 1500 mg of Metformin Hydrochloride Extended Release 750 mg, with a median value of 5 hours and a range of 4 to 12 hours.
Metformin Hydrochloride Extended Release 750 mg was proven in healthy fed and fasted volunteers to be bioequivalent to Metformin HCl ER 500 mg at a 1500 mg dose in terms of Cmax and AUC.
A single oral dosage of one tablet of Metformin HCl ER 1000 mg in the fed state results in a mean peak plasma concentration of 1214 ng/mL at a median time of 5 hours (range: 4 to 10 hours). Metformin HCl ER 1000 mg was proven in healthy fed and fasted subjects to be bioequivalent to Metformin HCl ER 500 mg at a 1000 mg dose in terms of Cmax and AUC.
When the 1000 mg extended release tablet is taken in fed settings, the AUC increases by 77% (Cmax increases by 26% and Tmax is somewhat delayed by around 1 hour).
Distribution: Plasma protein binding is insignificant. Metformin partitions into erythrocytes. The plasma peak is higher than the blood peak and appears almost simultaneously. The red blood cells most likely serve as a secondary compartment of distribution. The mean Vd ranged between 63-276 L.
Metabolism: Metformin is excreted unchanged in the urine. No metabolites have been found in humans.
Elimination: Metformin has a renal clearance of more than 400 mL/min, indicating that it is removed via glomerular filtration and tubular secretion. The apparent terminal elimination half-life after an oral dose is approximately 6.5 hours.
When renal function is reduced, renal clearance decreases in proportion to creatinine, causing the elimination half-life to be extended and metformin levels in plasma to rise.
Characteristics in specific group of patients: Renal impairment: There is a scarcity of data in participants with mild renal insufficiency, and no valid assessment of systemic metformin exposure in this subgroup compared to subjects with normal renal function could be performed. As a result, dose adjustments should be based on clinical efficacy/tolerability considerations.