Disposition of metformin (N,N‐dimethylbiguanide) in man

Abstract

Kinetic parameters ol metformin (N,N‐dimethylbiguanide), an anti‐diabetic reported to be associated with a lower number of episodes of lactic acidosis than phenformin, were determined in volunteers with normal renal function and in patients with different degrees ol renal impairment. Drug in body fluids was measured by a highly specific and sensitive mass fragmentographic method, alter the formation of a triazine derivative, obtained with heptafluorobutyric anhydride. The half‐life (t½) for the elimination ol drug from plasma after intravenous injection in 5 normal subjects (1.52 ± 0.3 hr) (mean ± SD) was shorter than that reported for phenformin by a similar assay method (7 to 15 hr). The mean t½ in 5 renal patients was 4.94 ± 1.11 hr, and a correlation was observed between t½ of drug from plasma and creatinine clearance. After oral administration of metlormin tablets, drug recovery in urines was only 37.6%, possibly not as a consequence of low bioavailability (a similar low recovery was found after oral administration of the metformin solution usedlor the intravenous studies), but of binding to the intestinal wall, as shown in animal and clinical studies with metformin and other biguanides. Metformin is rapidly eliminated through active secretion by the kidney (mean renal clearance, 440.8 ml/min)—it is neither metabolized nor protein‐bound in plasma. The very brief plasma t½ makes significant cumulation, with a standard tid regimen, unlikely. These findings may help explain the lower incidence of toxic effects, particularly lactic acidosis, than after phenformin.