Pharmacology of metformin

Metformin is rapidly absorbed after oral ingestion, with maximal plasma levels after about 2,5 hours. It is eliminated without modification by renal excretion, with a elimination half-time of about 6 hours. In the setting of renal insufficiency plasma half-life may be prolonged, and accumulation can occur.

Pharmacokinetics

[1] [2]Metformin is mainly absorbed in the small intestine. It has a bioavailability of 50–60% and it does not materially bind to plasma proteins. The maximum plasma concentration (Cmax) at usual dosages is about 1–2 µg/mL (~10 µmol/L) with steady-state plasma concentrations generally <1 µg/mL (<7.8 µmol/L). Metformin has a plasma elimination half-life of 6.2 h and it is renally eliminated both by filtration and active tubular secretion. It has been noted that metformin accumulates in the walls of the small intestine, in the salivary glands and in the kidney.

Use in patients with renal insufficiency

Because of its renal elimination and the putative risk of lactic acidosis when metformin accumulates, guidelines still recommend stopping metformin in cases of renal insufficiency, usually defined as an estimated glomerular filtration rate (eGFR) <30 mL/min per 1.73 m2. The few studies that have been performed seem to indicate that above this GFR cut-off value metformin doses of up to 1700mg are safe, but formal evidence that it is unsafe below the 30ml/min threshold is lacking. While it seems plausible that age and creatinine clearance are predictors of metformin levels, several authors have noted that it is difficult to establish a clear relation between metformin levels and lactic acid levels or between metformin levels and cases of lactic acidosis. For instance, in a review of 80 case reports published between 1959 and 1999, no clear causal relation could be identified by a panel of experts.[3] Thus, even if increased metformin levels were to occur this would not necessarily have clinical meaning. This explains why various studies have noted that renal insufficiency as a contraindication is increasingly disregarded, thusfar without adverse consequences.

Other reasons for discontinuing metformin use

Radiological interventions where contrast dyes are used are associated with an increased risk of acute renal insufficiency. Thus, as a precaution it is generally recommended to stop metformin prior to such investigations and to resume metformin use only when adequate renal function has been demonstrated (by checking serum creatinin) after 2-3 days. Likewise, interrupting metformin use is advocated in settings with increased lactic acid production, such as (septic) shock.

References

  1. ^ Garber AJ. Metformin and other pharmacology and therapeutic usage. Chapter 47. International Textbook of Diabetes Mellitus, 3rd edition. Edited by de Fronzo RA, Ferrannini E, Keen H, and Zimmet P. Wiley and Sons 2004.

  2. ^ Lipska KL et al. Use of Metformin in the Setting of Mild-to-Moderate Renal Insufficiency. Diab Care 2011;34(6)1431-37

  3. ^ Stades AME et al. Metformin and lactic cause or coincidence? A review of case reports. J Intern Med 2004;255(2)179-187.

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