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Pharmacology: Pharmacodynamics: Metformin is a biguanide with antihyperglycemic effects on 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) in the intestine, 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 glycemia, metformin has favorable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term clinical studies: 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.
Effect on body weight: In contrast to other commonly used antihyperglycemic agents, such as sulphonylureas or thiazolinediones, 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. The clinical studies conducted with metformin in both adults and children fully support that metformin improves glycemic control without increasing body weight or even with a small weight loss.
Pharmacokinetics: Absorption: Glucophage/Glucophage Forte: After an oral dose, maximum plasma concentration (Cmax) is reached in 2.5 hours (Tmax) between 1.5 and 3.5). Absolute bioavailability of a 500 mg or 850 mg metformin immediate-release tablet is approximately 50 to 60% in healthy subjects. After an oral dose, the non-absorbed fraction recovered in feces was 20 to 30%.
After oral administration, metformin absorption is saturable and incomplete. It is assumed that the pharmacokinetics of metformin absorption is non-linear.
At the usual metformin doses and dosing schedules, steady state plasma concentrations are reached within 24 to 48 hours and are generally less than 1 microgram/mL. In controlled clinical trials, maximum metformin plasma levels (Cmax) did not exceed 5 microgram/mL, even at maximum doses.
Food decreases the extent and slightly delays the absorption of metformin. Following administration of a dose of 850 mg, a 40% lower plasma peak concentration, a 25% decrease in AUC (area under the plasma concentration-time curve) and a 35 minute prolongation of time to peak plasma concentration were observed. The clinical relevance of these decreases is unknown.
Glucophage XR: After an oral dose of metformin (Glucophage XR) 500 mg, metformin absorption is significantly delayed compared to the immediate-release tablet (Tmax at 2.5 hours) with a Tmax at 7 hours.
Following a single oral administration of 1500 mg of metformin (Glucophage XR) 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. Metformin (Glucophage XR) 750 mg was shown to be bioequivalent to metformin (Glucophage XR) 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 metformin (Glucophage XR) 1 gram, a mean peak plasma concentration of 1214 ng/mL is achieved with a median time of 5 hours (range of 4 to 10 hours). Metformin (Glucophage XR) 1 gram was shown to be bioequivalent to metformin (Glucophage XR) 500 mg at a 1 gram dose with respect to Cmax and AUC in healthy fed and fasted subjects.
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 2 grams metformin extended release is similar to that observed after administration of 1 gram metformin immediate-release twice daily.
Intrasubject variability of Cmax and AUC of metformin extended release is comparable to that observed with metformin immediate-release.
When 2 tablets of 500 mg metformin extended release is administered in fed conditions the AUC is increased by approximately 70% (both Cmax and Tmax are only slightly increased).
When the 1 gram extended-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).
Metformin absorption from the extended-release formulation is not altered by meal composition.
No accumulation is observed after repeated administration of up to 2 grams metformin extended release.
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 to 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.
