Drug/Small Molecule:

glimepiride

Overview

Generic Names:	Glimepirid; Glimepirida; Glimepiridum; Glimepride
IUPAC Name:	3-ethyl-4-methyl-N-[2-[4-[(4-methylcyclohexyl)carbamoylsulfamoyl]phenyl]ethyl]-2-oxo-5H-pyrrole-1-carboxamide
Trade Names:	Amarel; Amaryl; Endial; Novo-glimepiride; PMS-glimepiride; Ratio-glimepiride; Sandoz glimepiride
Brand Mixtures:	Avandaryl (glimepiride + rosiglitazone maleate)
PharmGKB Accession Id:	PA449761

Description

Glimepiride is the first III generation sulphonyl urea it is a very potent sulphonyl urea with long duration of action.

Indication

For concomitant use with insulin for the treatment of noninsulin-dependent (type 2) diabetes mellitus.

ATC Therapeutic Category

• A10BB:Sulfonamides, urea derivatives

Pharmacology and Interactions

Mechanism Of Action

The mechanism of action of glimepiride in lowering blood glucose appears to be dependent on stimulating the release of insulin from functioning pancreatic beta cells, and increasing sensitivity of peripheral tissues to insulin. Glimepiride likely binds to ATP-sensitive potassium channel receptors on the pancreatic cell surface, reducing potassium conductance and causing depolarization of the membrane. Membrane depolarization stimulates calcium ion influx through voltage-sensitive calcium channels. This increase in intracellular calcium ion concentration induces the secretion of insulin.

Pharmacology

Glimepiride, like glyburide and glipizide, is a "second-generation" sulfonylurea agents. Glimepiride is used with diet to lower blood glucose by increasing the secretion of insulin from pancreas and increasing the sensitivity of peripheral tissues to insulin.

Food Interactions

Avoid alcohol. Even though food reduces product absorption, the manufacturer recommends taking the product with the first meal of the day.

Absorption, Distribution, Metabolism, Elimination & Toxicity

Biotransformation

Hepatic. Following either an intravenous or oral dose, glimepiride is completely metabolized by oxidative biotransformation to a major metabolite, cyclohexyl hydroxymethyl derivative (M1), via the hepatic cytochrome P450 II C9 subsystem. M1 is further metabolized to the carboxyl derivative (M2) by one or several cytosolic enzymes. M1, but not M2, possessed approximately one third of the pharmacologic activity of its parent in an animal model. However, whether the glucose-lowering effect of M1 is clinically significant is not clear.

Protein Binding

Over 99.5% bound to plasma protein.

Absorption

Completely (100%) absorbed following oral administration.

Half Life

Approximately 5 hours following single dose.

Toxicity

Severe hypoglycemic reactions with coma, seizure, or other neurological impairment.

Chemical Properties

Chemical Formula:

C₂₄H₃₄N₄O₅S

SMILES Code:

CCC1=C(CN(C1=O)C(=O)NCCC2=CC=C(C=C2)S(=O)(=O)NC(=O)N[C@H]3CC[C@@H](CC3)C)C

(Format: OpenEye Isomeric)

Molecular Weight ( average / monoisotopic )

490.616 / 490.225

Curated Annotations ()

1. rs1799853 at chr10:96692037 in CYP2C9
   In a study of Scottish patients receiving sulfonylureas (n=1073), those with any CYP2C9*2 alleles were less likely to experience treatment failure, and CYP2C9*2 homozygotes had greater reductions in HbA(1c) than CYP2C9*1.

   Variant Name:

   CYP2C9*2, CYP2C9:Arg144Cys

   Related Drugs:

   glibenclamide, gliclazide, glimepiride, glipizide, sulfonamides, urea derivatives

   Related Diseases:

   Diabetes Mellitus

   Evidence:

   PMID:19794412
   

2. rs1799853 at chr10:96692037 in CYP2C9
   Risk or phenotype-associated allele: CYP2C9*2, rs1799853 T allele, Cys144. Phenotype: Drug response phenotypes included (1) reaching target HbA(1c), (2) maximum HbA(1c) reduction, and (3) time to monotherapy failure. Patients homozygous for the loss-of-function CYP2C9 alleles (*2/*2, *2/*3, *3/*3) achieved greater treatment target (OR = 3.4, p = 0.0009), 0.5% greater reduction in target HbA1c concentration (p = 0.003), and lower risk of monotherapy failure based an additive genetic model (allelic hazard ratio 0.79, 95% confidence interval 0.63-0.99, p = 0.04), compared to wild-type allele (*1) carriers. Study size: 1,073 patients (578 drug-naive, 495 with prior and continued metformin exposure). Study population/ethnicity: Diabetes patients recruited in Tayside, Scotland for the Diabetes Audit and Research Tayside Study (DARTS), between 1992 and 2007, who were incident sulfonylurea users. Significance metric(s): p = (0.04 - 0.0009) Type of association: GN; PD

   Variant Name:

   CYP2C9*2, c.430C>T, mRNA 455C>T, p.Arg144Cys

   Related Drugs:

   glibenclamide, gliclazide, glimepiride, glipizide, metformin, sulfonamides, urea derivatives

   Related Diseases:

   Diabetes Mellitus, Type 2

   Evidence:

   PMID:19794412
   

3. rs1057910 at chr10:96731043 in CYP2C9
   In a study of Scottish patients receiving sulfonylureas (n=1073), those with any CYP2C9*3 alleles were less likely to experience treatment failure, and CYP2C9*3 homozygotes had greater reductions in HbA(1c) than CYP2C9*1.

   Variant Name:

   CYP2C9*3, CYP2C9:Ile359Leu

   Related Drugs:

   glibenclamide, gliclazide, glimepiride, glipizide, sulfonamides, urea derivatives

   Related Diseases:

   Diabetes Mellitus

   Evidence:

   PMID:19794412
   

4. rs1057910 at chr10:96731043 in CYP2C9
   Risk or phenotype-associated allele: CYP2C9*3, rs1057910 C allele, Leu359. Phenotype: Drug response phenotypes included (1) reaching target HbA(1c), (2) maximum HbA(1c) reduction, and (3) time to monotherapy failure. Patients homozygous for the loss-of-function CYP2C9 alleles (*2/*2, *2/*3, *3/*3) achieved greater treatment target (OR = 3.4, p = 0.0009), 0.5% greater reduction in target HbA1c concentration (p = 0.003), and lower risk of monotherapy failure based an additive genetic model (allelic hazard ratio 0.79, 95% confidence interval 0.63-0.99, p = 0.04), compared to wild-type allele (*1) carriers. Study size: 1,073 patients (578 drug-naive, 495 with prior and continued metformin exposure). Study population/ethnicity: Diabetes patients recruited in Tayside, Scotland for the Diabetes Audit and Research Tayside Study (DARTS), between 1992 and 2007, who were incident sulfonylurea users. Significance metric(s): p = (0.04 - 0.0009) Type of association: GN; PD

   Variant Name:

   CYP2C9*3, c.1075A>C, mRNA 11A>C, p.Ile359Leu

   Related Drugs:

   glibenclamide, gliclazide, glimepiride, glipizide, metformin, sulfonamides, urea derivatives

   Related Diseases:

   Diabetes Mellitus, Type 2

   Evidence:

   PMID:19794412
   

Curated Information

The following genes are in curated knowledge about this drug.

Non-Curated Information

A list of non-curated publications that mention this drug along with other genes is available.

Metabolizing Enzymes

• CYP2C9

Drug Targets

• KCNJ1
• KCNJ11

PharmGKB Curated Pathways

• Anti-diabetic drug pathway (Potassium channel inhibitors PD)

Non-Curated Information

A list of non-curated publications that mention this drug along with other drugs is available.

Drug Interactions

cyclosporine	The sulfonylurea increases the effect of cyclosporine
gemfibrozil	Gemfibrozil increases the effect and toxicity of rosiglitazone/pioglitazone
glucosamine	Possible hyperglycemia
ketoconazole	Ketoconazole increases the effect of rosiglitazone
pregabalin	Increased risk of edema
repaglinide	Similar mode of action - questionable association
rifampin	Rifampin reduces levels and efficacy of rosiglitazone, rifampin decreases the effect of sulfonylurea

Curated Information

The following diseases are in curated knowledge about this drug.

	Disease	Relationship	Evidence
	Diabetes Mellitus	PD       GN	Publications, Pathways
	Diabetes Mellitus, Type 2	CO          GN	Publications, Variants
	Hypoglycemia	CO          GN	Publications

Non-Curated Information

A list of non-curated publications that mention this drug along with other diseases is available.

Additional Datasets

These datasets are minimally curated and are sorted alphabetically by title.

1. Physicochemical determinants of human renal clearance
2. The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease

LinkOuts

Common Searches

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Non-Curated Publications

A list of non-curated publications that mention this drug is available.