Glyformet Extended Release Tablet Mechanism of Action

Pharmacotherapeutic Group: Oral Anti-Diabetics. ATC Code: (A10BA02: Gastrointestinal tract and metabolism).
Pharmacology: Pharmacodynamics: Metformin is a biguanide with antihyperglycaemic effects, lowering both basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia.
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 utilisation; 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.
In humans, independently of its action on glycaemia, immediate release metformin has favourable 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 prolonged release formulation, possibly due to the evening administration, and an increase in triglycerides may occur.
Pharmacokinetics: Absorption: After an oral dose of the prolonged 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 prolonged 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 prolonged release is comparable to that observed with metformin immediate release tablets.
When the prolonged release tablet is administered in fasting conditions the AUC is decreased by 30% (both Cmax and Tmax are unaffected).
Mean metformin absorption from the prolonged release formulation is almost not altered by meal composition.
No accumulation is observed after repeated administration of up to 2000 mg of metformin as prolonged release tablets.
Following a single oral administration of 1500 mg of Glucophage SR 750 mg, a mean peak plasma concentration of 1193 ng/mL is achieved with a median value of 5 hours and a range of 4 to 12 hours.
Glucophage SR 750 mg was shown to be bioequivalent to Glucophage SR 500 mg at a 1500 mg dose with respect to Cmax and AUC in healthy fed and fasted subjects.
Following a single oral administration in the fed state of one tablet of Glucophage SR 1000 mg, a mean peak plasma concentration of 1214 ng/mL is achieved with a median time of 5 hours (range of 4 to 10 hours).
Glucophage SR 1000 mg was shown to be bioequivalent to Glucophage SR 500 mg at a 1000 mg dose with respect to Cmax and AUC in healthy fed and fasted subjects.
When the 1000 mg prolonged release tablet is administered in fed conditions the AUC is increased by 77% (Cmax is increased by 26% and Tmax is slightly prolonged by about 1 hour).
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. The mean Vd ranged between 63-276 L.
Metabolism: Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.
Elimination: Renal clearance of metformin is >400 mL/min, 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.
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.
Characteristics in specific groups of patients: Renal impairment: The available data in subjects with moderate renal insufficiency are scarce and no reliable estimation of the systemic exposure to metformin in this subgroup as compared to subjects with normal renal function could be made. Therefore, the dose adaptation should be made upon clinical efficacy/tolerability considerations.