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Pharmacology: Metformin hydrochloride is an antihyperglycemic agent which improves glucose tolerance in NIDDM (type 2 diabetes mellitus) subjects, lowering both basal and postprandial plasma glucose. Its pharmacological mechanisms of action are different from those of sulfonylureas. Metformin decreases hepatic glucose production and improves insulin sensitivity (increases peripheral glucose uptake and utilization). Unlike sulfonylureas, Metformin does not produce hypoglycemia in either diabetic or nondiabetic subjects, and does not cause hyperinsulinemia. With Metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin levels may actually decrease.
Pharmacokinetics: Absorption and Bioavailability: Following a single oral dose of sustained-release Metformin, Cmax is achieved with a median value of 7 hours and a range of 4 hours to 8 hours. After repeated administration of a sustained-release formulation, Metformin does not accumulate in plasma. Although the extent of absorption of sustained-release Metformin is increased by approximately 50 % when given with food, there is no effect of food on Cmax and Tmax of Metformin.
Distribution: The apparent volume of distribution (V/F) of Metformin following single oral dose of 850 mg is 654±375 L. Metformin is negligibly bound to plasma proteins. At usual clinical doses and dosing schedules, steady state plasma concentrations of Metformin are reached within 24-48 hours and are generally <1 mg/mL.
Metabolism and Elimination: Metformin is excreted unchanged in the urine, and does not undergo hepatic metabolism or biliary excretion. Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of Metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 17.6 hours.
Special Populations: Patients with type 2 diabetes and Gender: There are no reported differences in pharmacokinetics of Metformin hydrochloride between patients with type 2 diabetes and normal subjects when analyzed according to gender.
Renal insufficiency: In patients with decreased renal function (based on measured creatinine clearance), the plasma and blood half-life of Metformin hydrochloride is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance. This increased level may lead to condition of lactic acidosis.
Hepatic insufficiency: No pharmacokinetic studies of Metformin hydrochloride have been conducted in patients with hepatic insufficiency.
Geriatrics: Reported data from controlled pharmacokinetic studies of Metformin hydrochloride in healthy elderly subjects suggest that total plasma clearance is decreased, the half-life is prolonged and Cmax is increased, compared to healthy young subjects. From this data, it appears that the change in Metformin hydrochloride pharmacokinetics with aging is primarily accounted for by a change in renal function.
Pediatrics: No pharmacokinetic studies of Metformin hydrochloride in pediatric patients have been conducted.
