GLIMEPIRIDE — glimepiride tablet
Physicians Total Care, Inc.
Glimepiride tablets USP are an oral blood-glucose-lowering drug of the sulfonylurea class. Glimepiride is a white to yellowish-white, crystalline, odorless to practically odorless powder formulated into tablets of 1 mg, 2 mg, and 4 mg strengths for oral administration. Glimepiride tablets USP contain the active ingredient glimepiride and the following inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate. In addition, glimepiride tablets USP 1 mg contain ferric oxide red, glimepiride tablets USP 2 mg contain ferric oxide yellow and FD&C Blue #2 aluminum lake, and glimepiride tablets USP 4 mg contain FD&C Blue #2 aluminum lake.
Chemically, glimepiride is identified as 1-[[p-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethyl]phenyl]sulfonyl]-3-(trans-4-methylcyclohexyl)urea.
The CAS Registry Number is 93479-97-1
The structural formula is:
C24 H34 N4 O5 S M.W. 490.62
Glimepiride is practically insoluble in water.
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. In addition, extrapancreatic effects may also play a role in the activity of sulfonylureas such as glimepiride. This is supported by both preclinical and clinical studies demonstrating that glimepiride administration can lead to increased sensitivity of peripheral tissues to insulin. These findings are consistent with the results of a long-term, randomized, placebo-controlled trial in which glimepiride therapy improved postprandial insulin/C-peptide responses and overall glycemic control without producing clinically meaningful increases in fasting insulin/C-peptide levels. However, as with other sulfonylureas, the mechanism by which glimepiride lowers blood glucose during long-term administration has not been clearly established.
Glimepiride is effective as initial drug therapy. In patients where monotherapy with glimepiride or metformin has not produced adequate glycemic control, the combination of glimepiride and metformin may have a synergistic effect, since both agents act to improve glucose tolerance by different primary mechanisms of action. This complementary effect has been observed with metformin and other sulfonylureas, in multiple studies.
A mild glucose-lowering effect first appeared following single oral doses as low as 0.5 to 0.6 mg in healthy subjects. The time required to reach the maximum effect (i.e., minimum blood glucose level [Tmin ]) was about 2 to 3 hours. In noninsulin-dependent (Type 2) diabetes mellitus (NIDDM) patients, both fasting and 2 hour postprandial glucose levels were significantly lower with glimepiride (1, 2, 4, and 8 mg once daily) than with placebo after 14 days of oral dosing. The glucose-lowering effect in all active treatment groups was maintained over 24 hours.
In larger dose-ranging studies, blood glucose and HbA1c were found to respond in a dose-dependent manner over the range of 1 to 4 mg/day of glimepiride. Some patients, particularly those with higher fasting plasma glucose (FPG) levels, may benefit from doses of glimepiride up to 8 mg once daily. No difference in response was found when glimepiride was administered once or twice daily.
In two 14 week, placebo-controlled studies in 720 subjects, the average net reduction in HbA1c for glimepiride tablet patients treated with 8 mg once daily was 2.0% in absolute units compared with placebo-treated patients. In a long-term, randomized, placebo-controlled study of Type 2 diabetic patients unresponsive to dietary management, glimepiride therapy improved postprandial insulin/C-peptide responses, and 75% of patients achieved and maintained control of blood glucose and HbA1c . Efficacy results were not affected by age, gender, weight, or race.
In long-term extension trials with previously-treated patients, no meaningful deterioration in mean fasting blood glucose (FBG) or HbA1c levels was seen after 2½ years of glimepiride therapy.
Combination therapy with glimepiride and insulin (70% NPH/30% regular) was compared to placebo/insulin in secondary failure patients whose body weight was > 130% of their ideal body weight. Initially, 5 to 10 units of insulin were administered with the main evening meal and titrated upward weekly to achieve predefined FPG values. Both groups in this double-blind study achieved similar reductions in FPG levels but the glimepiride/insulin therapy group used approximately 38% less insulin.
Glimepiride therapy is effective in controlling blood glucose without deleterious changes in the plasma lipoprotein profiles of patients treated for Type 2 diabetes.
After oral administration, glimepiride is completely (100%) absorbed from the GI tract. Studies with single oral doses in normal subjects and with multiple oral doses in patients with Type 2 diabetes 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).
After intravenous (IV) dosing in normal subjects, the volume of distribution (Vd) was 8.8 L (113 mL/kg), and the total body clearance (CL) was 47.8 mL/min. Protein binding was greater than 99.5%.
Glimepiride is completely metabolized by oxidative biotransformation after either an IV or oral dose. The major metabolites are the cyclohexyl hydroxy methyl derivative (M1) and the carboxyl derivative (M2). Cytochrome P450 2C9 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 in an
animal model; however, whether the glucose-lowering effect of M1 is clinically meaningful is not clear.
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 to 90% of that recovered in the urine. Approximately 40% of the total radioactivity was recovered in feces and M1 and M2 (predominant) accounted for about 70% of that recovered in feces. No parent drug was recovered from urine or feces. After IV dosing in patients, no significant biliary excretion of glimepiride or its M1 metabolite has been observed.
The pharmacokinetic parameters of glimepiride obtained from a single-dose, crossover, dose-proportionality (1, 2, 4, and 8 mg) study in normal subjects and from a single- and multiple-dose, parallel, dose-proportionality (4 and 8 mg) study in patients with Type 2 diabetes are summarized below:
|Volunteers||Patients With Type 2 Diabetes|
|Single Dose||Single Dose (Day 1)||Multiple Dose (Day 10)|
|Mean ± SD||Mean ± SD||Mean ± SD|
|1 mg||103 ± 34 (12)||—||—|
|2 mg||177 ± 44 (12)||—||—|
|4 mg||308 ± 69 (12)||352 ± 222 (12)||309 ± 134 (12)|
|8 mg||551 ± 152 (12)||591 ± 232 (14)||578 ± 265 (11)|
|Tmax (h)||2.4 ± 0.8 (48)||2.5 ± 1.2 (26)||2.8 ± 2.2 (23)|
|CL/f (mL/min)||52.1 ± 16.0 (48)||48.5 ± 29.3 (26)||52.7 ± 40.3 (23)|
|Vd/f (L)||21.8 ± 13.9 (48)||19.8 ± 12.7 (26)||37.1 ± 18.2 (23)|
|T1/2 (h)||5.3 ± 4.1 (48)||5.0 ± 2.5 (26)||9.2 ± 3.6 (23)|
( ) = No. of subjects
CL/f = Total body clearance after oral dosing
Vd/f = Volume of distribution calculated after oral dosing
These data indicate that glimepiride did not accumulate in serum, and the pharmacokinetics of glimepiride were not different in healthy volunteers and in Type 2 diabetic patients. Oral clearance of glimepiride did not change over the 1 to 8 mg dose range, indicating linear pharmacokinetics.
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