PHARMACOKINETICS AND PHARMACODYNAMICS OF METFORMIN IN HEALTHY-SUBJECTS AND PATIENTS WITH NONINSULIN-DEPENDENT DIABETES-MELLITUS

This study was conducted to assess the effect of noninsulin-dependent diabetes mellitus (NIDDM) and gender on the pharmacokinetics of metfor min and to investigate whether or not metformin exhibits dose-dependen t pharmacokinetics. The pharmacodynamic effects ion plasma glucose and insulin) of metformin in patients with NIDDM and in healthy subjects also were assessed. Nine patients with NIDDM and 9 healthy subjects re ceived 4 single-blind single-dose treatments of metformin HCl (850 mg, 1,700 mg 2,550 mg, and placebo) and a multiple-dose treatment of 850 mg metformin HCl (3 times daily for 19 doses). After each single-dose treatment and the final dose of the multiple-dose phase, multiple plas ma and urine samples were collected for 48 hours and assayed for metfo rmin levels. Plasma samples were also assayed for glucose and insulin levels. There were no significant differences in metformin kinetics in patients with NIDDM compared with healthy subjects, in men compared w ith women, or during multiple-dose treatment versus single-dose treatm ent. Plasma concentrations of metformin increase less than proportiona lly to dose, most likely due to a decrease in percent absorbed. in pat ients with NIDDM, single doses of 1,700-mg or higher of metformin sign ificantly decrease postprandial, but not preprandial, glucose concentr ations and do not influence insulin concentrations. With multiple dose s, both preprandial and postprandial glucose concentrations and prepra ndial insulin concentrations were significantly lower than with placeb o. The effect of metformin on glucose level is correlated with the ave rage fasting plasma glucose level without drug. In healthy subjects, s ingle and multiple doses of metformin showed no effect on plasma gluco se, but significantly attenuated the rise in immediate postprandial in sulin levels.