GLIMEPIRIDE 4MG & METFORMIN 1000MG SR
Glimepiride: The primary mechanism of action of glimepiride in lowering blood glucose appears to be dependent on stimulating the release of insulin from functioning pancreatic beta cells. .
Metformin: decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
Absorption Glimepiride: After oral administration, glimepiride is completely absorbed from the GI tract. Studies have shown significant absorption of glimepiride within 1 hour after administration and peak drug levels (Cmax) at 2 to 3 hours. When glimepiride was given with meals, the mean Tmax (time to reach Cmax) was slightly increased (12%) and the mean Cmax and AUC (area under the curve) were slightly decreased (8% and 9%, respectively).
Metformin sustained release: The absolute bioavailability of a metformin 500-mg tablet given under fasting conditions is approximately 50-60%. Following a single 2 oral dose of metformin sustained-release, Cmax is achieved within 4-8 hours. Peak plasma levels are approximately 20% lower compared to the same dose of metformin immediate release, however, the extent of absorption (as measured by AUC) is similar to immediate release. Both high and low fat meals had the same effect on the pharmacokinetics of extended release.
Glimepiride: After intravenous dosing in normal subjects, the volume of distribution (Vd) was 8.8 L (113 mL/kg). Protein binding was greater than 99.5%.
Metformin sustained release: Metformin is negligibly bound to plasma proteins, in contrast to sulphonylureas, 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 immediate-release metformin, steady state plasma concentrations of metformin are reached within 24-48 hours and are generally <1 μg/mL. During controlled clinical trials of immediate-release metformin, maximum metformin plasma levels did not exceed 5 μg/mL, even at maximum doses.
Glimepiride: Glimepiride is completely metabolized by oxidative biotransformation.The major metabolites are the cyclohexyl hydroxy methyl derivative (M1) and the carboxyl derivative (M2). Cytochrome P450 II C9 has been shown to be involved in the biotransformation of glimepiride to M1. M1 is further metabolized to M2 by one or several cytosolic enzymes. M1, but not M2, possesses about 1/3 of the pharmacological activity as compared to its parent; however, whether the glucoselowering effect of M1 is clinically meaningful is not clear.
Metformin sustained release: Metabolism studies with metformin sustainedrelease have not been conducted. However, intravenous single-dose studies in normal subjects demonstrate that metformin immediate release does not undergo hepatic metabolism or biliary excretion.
Excretion Glimepiride: When 14 C-glimepiride was given orally, approximately 60% of the total radioactivity was recovered in the urine in 7 days and M1 (predominant) and M2 accounted for 80-90% of that recovered in the urine. Approximately 40% of the total radioactivity was recovered in feces and M1 and M2 (predominant) accounted 3 for about 70% of that recovered in feces. No parent drug was recovered from urine or feces.
Metformin sustained release: 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 approximately 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.