Pharmacology: Pharmacodynamics: Metformin is a biguanide with antihyperglycaemic effects which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia. 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). 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- or long-term clinical studies: Immediate-release metformin reduces total cholesterol, low-density lipoprotein (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 time to maximum plasma concentration (Tmax) at 7 hrs (Tmax for the immediate-release tablet is 2.5 hrs). Peak plasma levels are approximateLy 20% lower compared to the same dose of immediate release. However, the extend of absorption [as measured by area under the concentration-time curve (AUC)] is similar to immediate released.
At steady state, similar to the immediate-release formulation, maximum plasma concentration (Cmax) and AUC are not proportionally increased to the administered dose.The AUC after a single oral administration of metformin 2000 mg prolonged-release tablets is similar to that observed after administration of metformin 1000 mg immediate-release tablets twice daily.
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).
Metformin absorption from the prolonged-release formulation is not altered by meal composition. No accumulation is observed after repeated administration of up to 2000 mg of metformin as prolonged-release tablets.
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 volume of distribution (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 hrs.
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.