Absorption
The absolute bioavailability of a Metformin hydrochloride 500 mg tablet given under fasting conditions is approximately 50 to 60%. Studies using single oral doses of Metformin hydrochloride 500 mg to 1500 mg, and 850 mg to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. Food decreases the extent of and slightly delays the absorption of Metformin, as shown by approximately a 40% lower mean peak plasma concentration (Cmax), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35 minute prolongation of time to peak plasma concentration (Tmax) following administration of a single 850 mg tablet of Metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.
Distribution
The apparent volume of distribution (V/F) of Metformin following single oral doses of Metformin hydrochloride 850 mg averaged 654 � 358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of Metformin, steady state plasma concentrations of Metformin are reached within 24 to 48 hours and are generally <1 �g/mL. During controlled clinical trials of Metformin, maximum Metformin plasma levels did not exceed 5 �g/mL, even at maximum doses.
Metabolism
Intravenous single-dose studies in normal subjects demonstrate that Metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion.
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 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.
Special Populations
Geriatric
Limited data from controlled pharmacokinetic studies of Metformin in healthy elderly subjects suggest that total plasma clearance of Metformin is decreased, the half-life is prolonged, and Cmax is increased, compared to healthy young subjects. From these data, it appears that the change in Metformin pharmacokinetics with aging is primarily accounted for by a change in renal function. Metformin treatment should not be initiated in patients ? 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced.
Pediatric
After administration of a single oral Metformin hydrochloride 500 mg tablet with food, geometric mean Metformin Cmax and AUC differed less than 5% between pediatric type 2 diabetic patients (12 to 16 years of age) and gender- and weight-matched healthy adults (20 to 45 years of age), all with normal renal function.
Gender
Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender (males = 19, females = 16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of Metformin hydrochloride tablets was comparable in males and females.
Race
No studies of Metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of Metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51), and Hispanics (n=24).
Renal Insufficiency
In patients with decreased renal function (based on measured creatinine clearance), the plasma and blood half-life of Metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance.
Hepatic Impairment
No pharmacokinetic studies of Metformin have been conducted in patients with hepatic insufficiency.
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