Metformin pharmacokinetics and molecular data

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Pharmacokinetics

Absorption & Bioavailability

Distribution

Metabolism and Elimination

Renal Insufficiency

Hepatic Insufficiency

Geriatrics



Absorption & Bioavailability

The absolute bioavailability of a Metformin 500-mg tablet given under fasting conditions is approximately 50-60%. Studies using single oral doses of Metformin 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 extent of metformin absorption (as measured by AUC) from Metformin at a 2000 mg once-daily dose is similar to the same total daily dose administered as Metformin tablets 1000 mg twice daily. After repeated administration of Metformin, metformin did not accumulate in plasma. Return to top

Distribution

The apparent volume of distribution (V/F) of metformin following single oral doses of Metformin 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 24-48 hours and are generally <1g/mL. During controlled clinical trials of Metformin, maximum metformin plasma levels did not exceed 5g/mL, even at maximum doses. Return to top

Metabolism and Elimination

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. Renal clearance (see Table 1) 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. Return to top

Patients with Type 2 Diabetes

In the presence of normal renal function, there are no differences between single- or multiple-dose pharmacokinetics of metformin between patients with type 2 diabetes and normal subjects (see Table 1), nor is there any accumulation of metformin in either group at usual clinical doses. The pharmacokinetics of Metformin in patients with type 2 diabetes are comparable to those in healthy normal adults. Return to top

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.Return to top

Hepatic Insufficiency

No pharmacokinetic studies of metformin have been conducted in patients with hepatic insufficiency. Return to top

Geriatrics

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. Return to top



Adapted from the FDA Package Insert.


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