Mechanism of Action
Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects (except in special circumstances, see PRECAUTIONS) and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.
Pharmacokinetics
Absorption and Bioavailability
The absolute bioavailability of a GLUCOPHAGE 500-mg tablet given under fasting conditions is approximately 50-60%. Studies using single oral doses of GLUCOPHAGE
500 mg to 1500 mg, and 850 mg to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an
alteration in elimination. Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration
(Cmax), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35 minute prolongation of time to peak plasma concentration (Tmax) following
administration of a single 850-mg tablet of metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.
Following a single oral dose of GLUCOPHAGE XR, Cmax is achieved with a median value of 7 hours and a range of 4 hours to 8 hours. Peak plasma levels are approximately
20% lower compared to the same dose of GLUCOPHAGE, however, the extent of absorption (as measured by AUC) is similar to GLUCOPHAGE.