GLIMEPRIDE 2MG & METFORMIN 500 MG + PIOGLITAZONE 15 MG
BRAND NAME: ZULIP- GP2 TABLET (Glimepride 2mg & Metformin 500 mg + Pioglitazone 15 mg)
COMPOSITION:-Each tablet contains Glimepride2mg,metformin500mg and pioglitazone15mg
Packing: – 10*10
Zulip-GP2 contains contains three oral anti-hyperglycemic drugs glimepiride, pioglitazone and metformin hydrochloride used in the management of type-2 diabetes (NIDDM).
a.) 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.
b.) Pioglitazone selectively stimulates the nuclear receptor peroxisome proliferatoractivated
receptor gamma (PPAR-γ) and to a lesser extent PPAR-. It modulates the
transcription of the insulin-sensitive genes involved in the control of glucose and
lipid metabolism in the muscle, adipose tissue, and the liver. As a result,
pioglitazone reduces insulin resistance in the liver and peripheral tissues; increases
the expense of insulin-dependent glucose; decreases withdrawal of glucose from the
liver; reduces quantity of glucose, insulin and glycated haemoglobin in the
c.) Metformin decreases hepatic glucose production, decreases intestinal absorption
of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake
The combination of glimepiride, pioglitazone and metformin sustained-release complements each other and provides better glycemic control in the management of type-2 diabetes and probably in the prevention of its associated macrovascular and microvascular complications.
2. Pharmacokinetics: –
a.) 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).
b.) Pioglitazone: Following oral administration, in the fasting state, pioglitazone is
first measurable in serum within 30 minutes, with peak concentrations observed within 2 hours. Food slightly delays the time to peak serum concentration [3 to 4hours], but does not alter the extent of absorption.
c.) 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.
a.) 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%.
b.) Pioglitazone: The mean apparent volume of distribution (Vd/F) of pioglitazone
following single dose administration is 0.63 ± 0.41 (mean ± SD) L/kg of body
weight. Pioglitazone is extensively protein bound (>99%) in human serum,
principally to serum albumin. Pioglitazone also binds to other serum proteins, but
with lower affinity. Metabolites M-III and M-IV also are extensively bound (>98%) to
c.) 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.
a.) 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.
b.) Pioglitazone: Pioglitazone is extensively metabolized by hydroxylation and
oxidation; the metabolites also partly convert to glucuronide or sulfate conjugates.
Metabolites M-II and M-IV (hydroxy derivatives of pioglitazone) and M-III (keto
derivative of pioglitazone) are pharmacologically active in animal models of type 2
diabetes. In addition to pioglitazone, M-III and M-IV are the principal drug-related
species found in human serum following multiple dosing. At steady-state, in both
healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises
approximately 30% to 50% of the total peak serum concentrations and 20% to 25%
of the total AUC. Urinary 6(beta)-hydroxycortisol/cortisol ratios measured in
patients treated with pioglitazone showed that pioglitazone is not a strong CYP3A4
c.) 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.
a.) 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.
b.) Pioglitazone: Following oral administration, approximately 15% to 30% of the pioglitazone dose is recovered in the urine. Renal elimination of pioglitazone is negligible, and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into the bile either unchanged or as metabolites and eliminated in the feces. The mean serum half-life of pioglitazone and total pioglitazone ranges from 3 to 7 hours and 16 to 24 hours, respectively. Pioglitazone has an apparent clearance, CL/F, calculated to be 5 to 7 L/hr.
c.) 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.
Glimitab MP Tablets are indicated once daily, as an adjunct to diet and exercise, to lower blood glucose. It is indicated as second-line therapy when diet, exercise, and the single agents or dual therapy do not result in adequate glycemic control in patients with type-2 diabetes.