Zyromet G Actions
Pharmacology: Pharmacodynamics: Zyromet G combines in a single dosage form, two antidiabetic agents with different mechanisms of action to improve glycemic control in patients with type 2 diabetes mellitus.
Metformin (Zyromet G) HCl: Metformin (Zyromet G) is a biguanide antidiabetic agent that reduces both basal and postprandial plasma glucose concentrations in patients with type 2 diabetes mellitus by improving both peripheral plasma glucose concentrations in patients with type 2 diabetes mellitus by improving both peripheral and hepatic sensitivity to insulin. It does not stimulate insulin secretion and therefore does not produce hypoglycemia when used alone. Fasting insulin levels and day-long insulin response remain the same or may even decrease with Metformin (Zyromet G) therapy.
Metformin (Zyromet G) Acts Via Three Mechanisms: It reduces hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis; increases insulin sensitivity in the skeletal muscles and adipocytes, improving peripheral glucose uptake and utilization; delays intestinal glucose absorption.
Metformin (Zyromet G) stimulates intracellular glycogen synthesis by acting on glycogen synthase. It also increases the transport capacity of all types of membrane glucose transporters.
Glimepiride (Zyromet G): It is a sulfonylurea antidiabetic agent and lowers blood glucose primarily by stimulating the release of insulin from functioning pancreatic β-cells.
Glimeperide also Exerts Extrapancreatic Effects in Two Ways: Rapidly increasing the number of active glucose transport molecules in the plasma membranes of the muscle and fat cells resulting in stimulated glucose uptake and by increasing the intracellular concentration of fructose-2, 6-biphosphate, resulting in the inhibition of glucose production (gluconeogenesis) in the liver. It also provides overall glycemic control by increasing the sensitivity of peripheral tissues to insulin.
Pharmacokinetics: A bioequivalence study in healthy volunteers have shown the fixed-dose combination (FDC) of Zyromet G to be bioequivalent to Metformin (Zyromet G) HCl 500 mg SR and Glimepiride (Zyromet G) 2 mg given as separate tablets with no serious adverse events reported during the study period. The following are the important pharmacokinetic parameters of Zyromet G SR tablet FDC given as a single oral dose under fasting conditions.
Metformin (Zyromet G) HCl: Metformin (Zyromet G) is slowly and incompletely absorbed from the gastrointestinal tract after oral administration. The absorption of Metformin (Zyromet G) HCl is significantly delayed compared to the immediate release formulation with the time to reach peak plasma concentration (Tmax) at 7 hrs (Tmax for the immediate-release tablet is 2.5 hrs). The absolute bioavailability of Metformin (Zyromet G) HCl doses of 500-1500 mg.
At steady-state, similar to immediate release formulation, peak plasma concentration (Cmax) and area under the concentration curve (AUC) of Metformin (Zyromet G) HCl SR show lack of dose proportionality with increasing doses. The extent of absorption from Metformin (Zyromet G) HCl SR at a 2,000 mg once daily is similar to the same total daily daily dose administered as Metformin (Zyromet G) immediate release tablets 1,000 mg twice daily.
Within subject variability in Cmax and AUC of Metformin (Zyromet G) HCl SR is comparable to that of Metformin (Zyromet G) immediate release.
Although the extent of absorption from Metformin (Zyromet G) HCl SR is increased by approximately 50% when given with food, there was no effect of food on Cmax and Tmax. Both high and low fat meals had the same effect on the pharmacokinetics of Metformin (Zyromet G) HCl SR.
Metformin (Zyromet G) distributes rapidly to peripheral body tissues and fluids. It also appears to distribute slowly into erythrocytes and into a deep tissue compartment. Metformin (Zyromet G) is negligibly bound to plasma proteins. Steady-state plasma concentration of Metformin (Zyromet G) is generally <1 mcg/mL and is reached within 24-48 hrs at usual clinical doses and dosing schedules.
Metformin (Zyromet G) is not metabolized in the liver or gastrointestinal tract (GIT). Renal elimination of Metformin (Zyromet G) is via glomerular filtration and secretion by the proximal convoluted tubules as unchanged drug. About 90% of the total dose is cleared within 24 hrs in patients with normal renal function.
Special Populations: Hepatic Insufficiency: There are no studies with the use of Metformin (Zyromet G) in patients with hepatic impairment. However, the use of Metformin (Zyromet G) in these patients has been associated with some cases of lactic acidosis. Its use in this population is therefore not recommended.
Renal Insufficiency: There plasma and blood half-life (t½) of Metformin (Zyromet G) is prolonged and the renal clearance decreased in proportion to the decrease in creatinine clearance (CrCl) in patients with decreased renal function (based on measured creatinine levels).
Elderly: The limited pharmacokinetic data of Metformin (Zyromet G) in healthy elderly subjects suggest that total plasma clearance of Metformin (Zyromet G) is decreased, t½ is prolonged and Cmax is increased, compared to healthy young subjects. It appears that the change in Metformin (Zyromet G) pharmacokinetics with aging is primarily related to a change in renal function.
Glimepiride (Zyromet G): Glimepiride (Zyromet G) is completely (100%) absorbed from the gastrointestinal tract after oral administration. Cmax is reached in about 2-3 hrs. Tmax was slightly increased (12%) and the mean Cmax and AUC were slightly decreased (8% and 9%, respectively) when Glimepiride (Zyromet G) was given with meals.
Glimepiride (Zyromet G) has a very low volume of distribution (about 8.8 L), high protein binding (>99.5%) and low total body clearance (approximately 48 mL/min). It is likely to be only minimally removed by hemodialysis. Glimepiride (Zyromet G) is excreted in milk in animals. It is transferred to the placenta and passage of the blood brain barrier is low.
Glimepiride (Zyromet G) is completely metabolized by oxidative transformation via the hepatic cytochrome P450 II C9 subsystem with major metabolites, M-I and M-II. M-I has 1/3 the pharmacologic activity of its parent compound. However, it is not clear whether the glucose-lowering effect of M-I is clinically significant.
About 60% of Glimepiride (Zyromet G) is recovered in the urine within 7 days with M-I (predominant) and M-II accounting for 80-90% of that recovered. About 40% is recovered in the feces; M-I and M-II (predominant) account for 70% of that recovered in the feces. No parent drug is recovered from urine or feces. The terminal t½ of these metabolites were 3-6 and 5-6 hrs, respectively.
Significant biliary excretion of Glimepiride (Zyromet G) or its M1 metabolite is not observed after IV dosing.
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Information checked by Dr. Sachin Kumar, MD Pharmacology