CLINICAL PHARMACOKINETICS OF METFORMIN

The biguanide metformin (dimethylbiguanide) is an oral antihyperglycae mic agent widely used in the management of non-insulin-dependent diabe tes mellitus (NIDDM), Considerable renewal of interest in this drug ha s been observed in recent years. Metformin can be determined in biolog ical fluids by various methods, mainly using high performance liquid c hromatography, which allows pharmacokinetic studies in healthy volunte ers and diabetic patients. Metformin disposition is apparently unaffec ted by the presence of diabetes and only slightly affected by the use of different oral formulations. Metformin has an absolute oral bioavai lability of 40 to 60%, and gastrointestinal absorption is apparently c omplete within 6 hours of ingestion. An inverse relationship was obser ved between the dose ingested and the relative absorption with therape utic doses ranging from 0.5 to 1.5g, suggesting the involvement of an active, saturable absorption process. Metformin is rapidly distributed following absorption and does not bind to plasma proteins. No metabol ites or conjugates of metformin have been identified. The absence of l iver metabolism clearly differentiates the pharmacokinetics of metform in from that of other biguanides, such as phenformin. Metformin underg oes renal excretion and has a mean plasma elimination half-life after oral administration of between 4.0 and 8.7 hours. This elimination is prolonged in patients with renal impairment and correlates with creati nine clearance. There are only scarce data on the relationship between plasma metformin concentrations and metabolic effects. Therapeutic le vels may be 0.5 to 1.0 mg/L in the fasting state and 1 to 2 mg/L after a meal, but monitoring has little clinical value except when lactic a cidosis is suspected or present. Indeed, when lactic acidosis occurs i n metformin-treated patients, early determination of the metformin pla sma concentration appears to be the best criterion for assessing the i nvolvement of the drug in this acute condition. After confirmation of the diagnosis, treatment should rapidly involve forced diuresis or hae modialysis, both of which favour rapid elimination of the drug. Althou gh serious, lactic acidosis due to metformin is rare and may be minimi sed by strict adherence to prescribing guidelines and contraindication s, particularly the presence of renal failure. Finally, only very few drug interactions have been described with metformin in healthy volunt eers. Plasma levels may be reduced by guar gum and alpha-glucosidase i nhibitors and increased by cimetidine, but no data are yet available i n the diabetic population.