Pharmacokinetics and Pharmacodynamics of Metformin in Healthy Subjects and Patients with Noninsulin‐Dependent Diabetes Mellitus

Abstract

This study was conducted to assess the effect of noninsulin-dependent diabetes mellitus (NIDDM) and gender on the pharmacokinetics of metformin and to investigate whether or not metformin exhibits dose-dependent pharmacokinetics. The pharmacodynamic effects (on 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 received 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 plasma and urine samples were collected for 48 hours and assayed for metformin 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 with women, or during multiple-dose treatment versus single-dose treatment. Plasma concentrations of metformin increase less than proportionally to dose, most likely due to a decrease in percent absorbed. In patients with NIDDM, single doses of 1,700-mg or higher of metformin significantly decrease postprandial, but not preprandial, glucose concentrations and do not influence insulin concentrations. With multiple doses, both preprandial and postprandial glucose concentrations and preprandial insulin concentrations were significantly lower than with placebo. The effect of metformin on glucose level is correlated with the average fasting plasma glucose level without drug. In healthy subjects, single and multiple doses of metformin showed no effect on plasma glucose, but significantly attenuated the rise in immediate postprandial insulin levels.

Metformin Suppresses Systemic Autoimmunity in Roquinsan/san Mice through Inhibiting B Cell Differentiation into Plasma Cells via Regulation of AMPK/mTOR/STAT3

“…2B). Although metformin has been widely used to control blood glucose levels in patients with type 2 diabetes, it was reported that it has no effect on blood glucose levels in nondiabetic human subjects (25).…”

Comparative Pharmacokinetic Study between Metformin Alone and Combined with Orlistat in Healthy Mexican Volunteers

“…Pharmacokinetic results obtained in the current study showed conclusive data with respect to therapeutic equivalence since the comparison between the test formulation (metformin-orlistat) and the reference formulation (metformin) for Cmax and AUC 24h showed percentages that fall in the rank of equivalence. These pharmacokinetic parameters are according to those reported in previous studies [14][15][16][17][18][19].…”

“…Metfomin is mainly absorbed in the small intestine, it has an oral bioavailability of 50% -60% under fasting conditions, its plasma protein binding is negligible, as reflected by its very high apparent volume of distribution. It is not metabolized by liver and ~90% is excreted unchanged in the urine [14][15][16][17][18][19].…”

Dose-dependent relationship between serum metformin levels and glycemic control, insulin resistance and leptin levels in females newly diagnosed with type 2 diabetes mellitus

“…Consequently, the greater fluctuation of plasma concentrations should not be clinically significant, as has been observed in the present study. Metformin exhibits flip-flop kinetics, where the slow absorption of metformin is the rate-limiting factor in its disposition, and clinical trials with metformin have demonstrated decreased bioavailability at higher doses, suggesting saturable intestinal absorption [9], and accordingly we can explain the non-significant differences between average steady state plasma concentrations after administration of increased doses. In type 2 DM patients, metformin was demonstrated to have no effect in erythrocyte insulin receptor binding, but it increased both basal and insulin stimulated insulin receptor tyrosine kinase activities of solubilized erythrocyte insulin receptors after 10 wk of treatment [24].…”

“…Thus, its passage across cell membranes is heavily dependent on transporters, and intestinal absorption of metformin is dose dependent and involves an active, saturable uptake process [7], while its plasma protein binding is negligible [8]. Moreover, the bioavailability of metformin is not complete, and large interindividual differences in bioavailability after oral administration in the range of 20% -70% have been described [9]. The clinical effects of metformin develop slowly over several days of treatment at least [10] and the range of plasma concentrations over a dosage interval depends upon the formulation without any significant effect on the clinical response [11].…”