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At steady state, the AUC and C max are less than dose proportional for GLUCOPHAGE XR within the range of 500 mg to 2000 mg administered once daily. Peak plasma levels are approximately 0.6, 1.1, 1.4, and 1.8 µg/ mL for 500, 1000, 1500, and 2000 mg once-daily doses, respectively. The extent of metformin absorption (as measured by AUC) from GLUCOPHAGE XR at a 2000 mg once-daily dose is similar to the same total daily dose administered as GLUCOPHAGE tablets 1000 mg twice daily. After repeated administration of GLUCOPHAGE XR, metformin did not accumulate in plasma. Within-subject variability in C max and AUC of metformin from GLUCOPHAGE XR is comparable to that with GLUCOPHAGE. Although the extent of metformin absorption (as measured by AUC) from the GLUCOPHAGE XR tablet increased by approximately 50% when given with food, there was no effect of food on C max and T max of metformin. Both high and low fat meals had the same effect on the pharmacokinetics of GLUCOPHAGE XR. Text Continues Below
Distribution The apparent volume of distribution (V/ F) of metformin following single oral doses of GLUCOPHAGE 850 mg averaged 654± 358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of GLUCOPHAGE, steady state plasma concentrations of metformin are reached within 24-48 hours and are generally < 1 g/ mL. During controlled clinical trials of GLUCOPHAGE, maximum met-formin plasma levels did not exceed 5 g/ mL, even at maximum doses. Metabolism and Elimination Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been iden-tified in humans) nor biliary excretion. Renal clearance (see Table 1) is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approx-imately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution. Page: << Prev | 1 | 2 | 3 | 4 | 5 | Next >>
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