Glimepiride-d4 (phenylethyl-α,α,β,β-d4) (cis/trans)

490.62

490.22499137 g/mol

6KY687524K|24T6XIR2MZ

759809

DTXSID5040675

C29073

A10BD06|A10BD04|A10BB12|A - Alimentary tract and metabolism

133 Ų

3.5

1.29±0.1 g/cm3(Predicted)

207°C

>73.6 [ug/mL]|Partly miscible|3.84e-02 g/L

5.10±0.10(Predicted)

216.6 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]

|Danger|H301 (50%): Toxic if swallowed [Danger Acute toxicity, oral]|P201, P202, P261, P264, P270, P271, P280, P281, P301+P310, P302+P352, P304+P340, P305+P351+P338, P308+P313, P311, P321, P330, P332+P313, P337+P313, P362, P403+P233, P405, and P501|Aggregated GHS information provided by 6 companies from 6 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

The oral LD50 value in rats is > 10000 mg/kg.[MSDS] The intraperitoneal LD50 value in rats is reported to be 3950 mg/kg [MSDS]. Although glimepiride is reported to have fewer risks of hypoglycemia compared to other sulfonylureas such as glyburide, overdosage of glimepiride may result in severe hypoglycemia with coma, seizure, or other neurological impairment may occur. This can be treated with glucagon or intravenous glucose. Continued observation and additional carbohydrate intake may be necessary since hypoglycemia may recur after apparent clinical recovery. In a study of rats given doses of up to 5000 parts per million (ppm) in complete feed for 30 months, there were no signs of carcinogenesis. Meanwhile, the administration of glimepiride at a dose much higher than the maximum human recommended dose for 24 months in mice resulted in an increase in benign pancreatic adenoma formation in a dose-related manner, which was thought to be the result of chronic pancreatic stimulation. Glimepiride was non-mutagenic in _in vitro_ and _in vivo_ mutagenicity studies. In male and female rat studies, glimepiride was shown to have no effects on fertility.

Neither normal nor excessively high intakes of vitamin E are associated with liver injury or liver test abnormalities. In long term clinical trials, serum enzyme and bilirubin elevations were no more frequent with vitamin E therapy than with placebo. Indeed, in many animal models, vitamin E is protective against hepatotoxic substances and provides antioxidant and cytoprotective activity to hepatocytes. In several randomized controlled trials, vitamin E has been found to improve serum aminotransferase elevations and liver biopsy histologic findings of steatosis, inflammation and cell injury in patients with nonalcoholic steatohepatitis (NASH). Therapy was well tolerated and no patients had significant rises in serum aminotransferase levels during treatment or worsening of the underlying liver injury. While liver histology improved including steatosis, cell injury and inflammation, therapy was not associated with improvements in liver fibrosis and the role of vitamin E in the long term management of nonalcoholic fatty liver disease is not clear. However, in multiple controlled trials of vitamin E therapy there have been no reports of significant liver injury or jaundice with treatment.

Plasma protein binding of glimepiride is greater than 99.5%.

Glimepiride is indicated for the management of type 2 diabetes in adults as an adjunct to diet and exercise to improve glycemic control as monotherapy. It may also be indicated for use in combination with metformin or insulin to lower blood glucose in patients with type 2 diabetes whose high blood sugar levels cannot be controlled by diet and exercise in conjunction with an oral hypoglycemic (a drug used to lower blood sugar levels) agent alone.|Tandemact is indicated for the treatment of patients with type-2 diabetes mellitus who show intolerance to metformin or for whom metformin is contraindicated and who are already treated with a combination of pioglitazone and glimepiride.,|AVAGLIM is indicated in the treatment of type 2 diabetes mellitus patients who are unable to achieve sufficient glycaemic control on optimal dosage of sulphonylurea monotherapy, and for whom metformin is inappropriate because of contraindication or intolerance.|Treatment of hyperlipidaemia, Treatment of type II diabetes mellitus

Vitamin E (alpha tocopherol) is a fat soluble vitamin and potent antioxidant that is believed to be important in protecting cells from oxidative stress, regulating immune function, maintaining endothelial cell integrity and balancing normal coagulation. There is no evidence that vitamin E, in physiologic or even super-physiologic, high doses, causes liver injury or jaundice.

Vitamins

Glimepiride stimulates the secretion of insulin granules from the pancreatic beta cells and improves the sensitivity of peripheral tissues to insulin to increase peripheral glucose uptake, thus reducing plasma blood glucose levels and glycated hemoglobin (HbA1C) levels. A multi-center, randomized, placebo-controlled clinical trial evaluated the efficacy of glimepiride (1–8 mg) as monotherapy titrated over 10 weeks compared with placebo in T2DM subjects who were not controlled by diet alone. In this study, there was a reduction in fasting plasma glucose (FPG) by 46 mg/dL, post-prandial glucose (PPG) by 72 mg/dL, and HbA1c by 1.4% more than the placebo. In another randomized study comprising of patients with T2DM receiving either placebo or one of the three doses (1, 4, or 8 mg) of glimepiride during a 14-week study period, all glimepiride regimens significantly reduced FPG, PPG, and HbA1c values (P < 0.001) compared to placebo by the end of the study period. The 4- and 8-mg doses of glimepiride were more effective than the 1-mg dose; however, the 4-mg dose provided a nearly maximal antihyperglycemic effect.

Agents used for the treatment or prevention of cardiac arrhythmias. They may affect the polarization-repolarization phase of the action potential, its excitability or refractoriness, or impulse conduction or membrane responsiveness within cardiac fibers. Anti-arrhythmia agents are often classed into four main groups according to their mechanism of action: sodium channel blockade, beta-adrenergic blockade, repolarization prolongation, or calcium channel blockade. (See all compounds classified as Anti-Arrhythmia Agents.)|Substances which lower blood glucose levels. (See all compounds classified as Hypoglycemic Agents.)|Agents that suppress immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others may act through activation of T-CELLS or by inhibiting the activation of HELPER CELLS. While immunosuppression has been brought about in the past primarily to prevent rejection of transplanted organs, new applications involving mediation of the effects of INTERLEUKINS and other CYTOKINES are emerging. (See all compounds classified as Immunosuppressive Agents.)

Glimepiride is completely absorbed after oral administration within 1 hour of administration with a linear pharmacokinetics profile. Following administration of a single oral dose of glimepiride in healthy subjects and with multiple oral doses with type 2 diabetes, the peak plasma concentrations (Cmax) were reached after 2 to 3 hours post-dose. Accumulation does not occur after multiple doses. When glimepiride was given with meals, the time to reach Cmax was increased by 12% while the mean and AUC (area under the curve) were decreased by 8 to 9%, respectively. In a pharmacokinetic study of Japanese patients with T2DM, Cmax value in once-daily dose was higher than those in twice-daily doses. The absolute bioavailability of glimepiride is reported to be complete following oral administration.|Following oral administration of glimepiride in healthy male subjects, approximately 60% of the total radioactivity was recovered in the urine in 7 days, with M1 and M2 accounting for 80-90% of the total radioactivity recovered in the urine. The ratio of M1 to M2 was approximately 3:2 in two subjects and 4:1 in one subject. Approximately 40% of the total radioactivity was recovered in feces where M1 and M2 accounted for about 70% of the radioactivity and a ratio of M1 to M2 being 1:3. No parent drug was recovered from urine or feces.|Following intravenous dosing in healthy subjects, the volume of distribution was 8.8 L (113 mL/kg).|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 (T2D) were performed. In these studies, the total body clearance was 52.1 +/- 16.0 mL/min, 48.5 +/- 29.3 mL/min in patients with T2D given a single oral dose, and 52.7 +/- 40.3 mL/min in patients with T2D given multiple oral doses. Following intravenous dosing in healthy subjects, the total body clearance was 47.8 mL/min.

Glimepiride is reported to undergo hepatic metabolism. Following either an intravenous or oral dose, glimepiride undergoes oxidative biotransformation mediated by CYP2C9 enzyme to form a major metabolite, cyclohexyl hydroxymethyl derivative (M1), that is pharmacologically active. M1 can be further metabolized to the inactive metabolite carboxyl derivative (M2) by one or several cytosolic enzymes. M1 retained approximately one third of the pharmacologic activity of its parent in an animal model, with a half-life of 3-6 hours. However, whether the glucose-lowering effect of M1 is clinically significant is not clear.|Glimepiride has known human metabolites that include Cyclohexylhydroymethylglimepiride.

The elimination half-life of glimepiride is approximately 5 to 8 hours, which can increase up to 9 hours following multiple doses.

ATP-sensitive potassium channels on pancreatic beta cells that are gated by intracellular ATP and ADP. The hetero-octomeric complex of the channel is composed of four pore-forming Kir6.2 subunits and four regulatory sulfonylurea receptor (SUR) subunits. Alternative splicing allows the formation of channels composed of varying subunit isoforms expressed at different concentrations in different tissues. In pancreatic beta cells, ATP-sensitive potassium channels play a role as essential metabolic sensors and regulators that couple membrane excitability with glucose-stimulated insulin secretion (GSIS). When there is a decrease in the ATP:ADP ratio, the channels are activated and open, leading to K+ efflux from the cell, membrane hyperpolarization, and suppression of insulin secretion. In contrast, increased uptake of glucose into the cell leads to elevated intracellular ATP:ADP ratio, leading to the closure of channels and membrane depolarization. Depolarization leads to activation and opening of the voltage-dependent Ca2+ channels and consequently an influx of calcium ions into the cell. Elevated intracellular calcium levels causes the contraction of the filaments of actomyosin responsible for the exocytosis of insulin granules stored in vesicles. Glimepiride blocks the ATP-sensitive potassium channel by binding non-specifically to the B sites of both sulfonylurea receptor-1 (SUR1) and sulfonylurea receptor-2A (SUR2A) subunits as well as the A site of SUR1 subunit of the channel to promote insulin secretion from the beta cell.

1-(4-(2-(3-ethyl-4-methyl-2-oxo-3-pyrrolinecarboxamido)ethyl)phenylsulfonyl)-3-(4-methylcyclohexyl)urea

Human drugs -> Tandemact -> EMA Drug Category|Drugs used in diabetes -> Human pharmacotherapeutic group|Human drugs -> Avaglim -> EMA Drug Category|Human Drugs -> EU pediatric investigation plans|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients