Drug/Small Molecule:
gliclazide

Dutch Pharmacogenetics Working Group Guideline - gliclazide, CYP2C9
Genotype Therapeutic Dose Recommendation Level of Evidence Clinical Relevance
CYP2C9 *1/*2 None Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. Clinical effect (NS) Kinetic effect (NS)
CYP2C9 *2/*2 None Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. Clinical effect (NS) Kinetic effect (NS)
CYP2C9 *1/*3 None Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. Clinical effect (NS) Kinetic effect (NS)
CYP2C9 *2/*3 None Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. Clinical effect (NS) Kinetic effect (NS)
CYP2C9 *3/*3 None Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. Clinical effect (NS) Kinetic effect (NS)
  • *See Methods or PMID: 18253145 for definition of "moderate" quality.
  • S: statistically significant difference.
  • NS: non-significant

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The table below contains information about pharmacogenomic variants on PharmGKB. Please follow the link in the "Variant" column for more information about a particular variant. Each link in the "Variant" column leads to the corresponding PharmGKB Variant Page. The Variant Page contains summary data, including PharmGKB manually curated information about variant-drug pairs based on individual PubMed publications. The PMIDs for these PubMed publications can be found on the Variant Page.

The tags in the first column of the table indicate what type of information can be found on the corresponding Variant Page.

Links in the "Gene" column lead to PharmGKB Gene Pages.

Gene ? Variant?
(build 132) 		Alternate Names ? Drugs ? Alleles ?
(+ chr strand) 		Function ? Amino Acid?
Translation
No VIP available No Clinical Annotations available VA
rs1057910 CYP2C9*3, CYP2C9*3:Ile359Leu, CYP2C9: I359L, CYP2C9:359Ile>Leu, CYP2C9:Ile359Leu, c.1075A>C, g.47545517A>C, g.47639A>C, g.96731043A>C, mRNA 11A>C, p.Ile359Leu
A > T
A > C
A > G
 Missense
Ile359Leu
No VIP available No Clinical Annotations available VA
rs1799853 CYP2C9*2, CYP2C9:144Arg>Cys, CYP2C9:Arg144Cys, c.430C>T, g.47506511C>T, g.8633C>T, g.96692037C>T, mRNA 455C>T, p.Arg144Cys
C > G
C > T
C > A
 Missense
Arg144Cys
Alleles, Functions, and Amino Acid Translations are all sourced from dbSNP build 132
2D structure

Overview

Generic Names
  • 1-(3-Azabicyclo(3.3.0)oct-3-yl)-3-(p-tolylsulfonyl)urea
  • 1-(Hexahydrocyclopenta(c)pyrrol-2(1H)-yl)-3-(p-tolylsulfonyl)urea
  • Gliclazida [INN-Spanish]
  • Gliclazidum [INN-Latin]
  • N-(4-Methylbenzenesulfonyl)-N'-(3-azabicyclo(3.3.0)oct-3-yl)urea
Trade Names
  • Diamicron
  • Diamicron MR
  • Glimicron
  • Mylan-Gliclazide
  • Nordialex
  • PMS-Gliclazide
Brand Mixture Names

PharmGKB Accession Id:
PA10892

Description

Gliclazide is an oral antihyperglycemic agent used for the treatment of non-insulin-dependent diabetes mellitus (NIDDM). It belongs to the sulfonylurea class of insulin secretagogues, which act by stimulating β cells of the pancreas to release insulin. Sulfonylureas increase both basal insulin secretion and meal-stimulated insulin release. Medications in this class differ in their dose, rate of absorption, duration of action, route of elimination and binding site on their target pancreatic β cell receptor. Sulfonylureas also increase peripheral glucose utilization, decrease hepatic gluconeogenesis and may increase the number and sensitivity of insulin receptors. Sulfonylureas are associated with weight gain, though less so than insulin. Due to their mechanism of action, sulfonylureas may cause hypoglycemia and require consistent food intake to decrease this risk. The risk of hypoglycemia is increased in elderly, debilitated and malnourished individuals. Gliclazide has been shown to decrease fasting plasma glucose, postprandial blood glucose and glycosolated hemoglobin (HbA1c) levels (reflective of the last 8-10 weeks of glucose control). Gliclazide is extensively metabolized by the liver; its metabolites are excreted in both urine (60-70%) and feces (10-20%).

Source: Drug Bank

Indication

For the treatment of NIDDM in conjunction with diet and exercise.

Source: Drug Bank

ATC Therapeutic Category

  • A10BB:Sulfonamides, urea derivatives

Information pulled from DrugBank has not been reviewed by PharmGKB.

Pharmacology, Interactions, and Contraindications

Mechanism of Action

Gliclazide binds to the β cell sulfonyl urea receptor (SUR1). This binding subsequently blocks the ATP sensitive potassium channels. The binding results in closure of the channels and leads to a resulting decrease in potassium efflux leads to depolarization of the β cells. This opens voltage-dependent calcium channels in the β cell resulting in calmodulin activation, which in turn leads to exocytosis of insulin containing secretorty granules.

Source: Drug Bank

Pharmacology

Gliclazide is a second generation sulphonylurea which acts as a hypoglycemic agent. It stimulates β cells of the islet of Langerhans in the pancreas to release insulin. It also enhances peripheral insulin sensitivity. Overall, it potentiates insulin release and improves insulin dynamics.

Source: Drug Bank

Food Interaction

Avoid alcohol.|Take without regard to meals. A consistent diet is recommended to reduce the risk of hypoglycemia.

Source: Drug Bank

Absorption, Distribution, Metabolism, Elimination & Toxicity

Biotransformation

Extensively metabolized in the liver. Less than 1% of the orally administered dose appears unchanged in the urine. Metabolites include oxidized and hydroxylated derivates, as well as glucuronic acid conjugates.

Source: Drug Bank

Protein Binding

94%, highly bound to plasma proteins

Source: Drug Bank

Absorption

Rapidly and well absorbed but may have wide inter- and intra-individual variability. Peak plasma concentrations occur within 4-6 hours of oral administration.

Source: Drug Bank

Half-Life

10.4 hours. Duration of action is 10-24 hours.

Source: Drug Bank

Toxicity

LD50=3000 mg/kg (orally in mice). Gliclazide and its metabolites may accumulate in those with severe hepatic and/or renal dysfunction. Symptoms of hypoglycemia include: dizziness, lack of energy, drowsiness, headache and sweating.

Source: Drug Bank

Route of Elimination

Metabolites and conjugates are eliminated primarily by the kidneys (60-70%) and also in the feces (10-20%).

Source: Drug Bank

Chemical Properties

Chemical Formula

C15H21N3O3S

Source: Drug Bank

Canonical SMILES

CC1=CC=C(C=C1)S(=O)(=O)NC(=O)NN1CC2CCCC2C1

Source: Drug Bank

Average Molecular Weight

323.411

Source: Drug Bank

Monoisotopic Molecular Weight

323.130362243

Source: Drug Bank

Genes that are associated with this drug in PharmGKB's database based on (1) variant annotations, (2) literature review, (3) pathways or (4) information automatically retrieved from DrugBank, depending on the "evidence" and "source" listed below.

Curated Information ?

EvidenceGene
DG No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
CYP2C9
No related drugs are available.

Curated Information ?

EvidenceDisease
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
Diabetes Mellitus, Type 2

Publications related to gliclazide: 8

No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Genetic risk factors for type 2 diabetes mellitus and response to sulfonylurea treatment. Pharmacogenetics and genomics. 2011. Swen Jesse J, et al. [Article:21633322@PubMed]
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Loss-of-function CYP2C9 variants improve therapeutic response to sulfonylureas in type 2 diabetes: a Go-DARTS study. Clinical pharmacology and therapeutics. 2010. Zhou K, et al. [Article:19794412@PubMed]
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
Effect of CYP2C9 polymorphisms on prescribed dose and time-to-stable dose of sulfonylureas in primary care patients with Type 2 diabetes mellitus. Pharmacogenomics. 2010. Swen Jesse J, et al. [Article:21121772@PubMed]
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Presence of CYP2C9*3 allele increases risk for hypoglycemia in Type 2 diabetic patients treated with sulfonylureas. Pharmacogenomics. 2009. Ragia Georgia, et al. [Article:19891554@PubMed]
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Pharmacogenetics of glucose-lowering drug treatment: a systematic review. Molecular diagnosis & therapy. 2007. Bozkurt Ozlem, et al. [Article:17963417@PubMed]
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Lymphocyte ecto-5'-nucleotidase in obese type 2 diabetic patients treated with gliclazide. Diabetes & metabolism. 2006. Stefanovic V, et al. [Article:16735966@PubMed]
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Differential selectivity of insulin secretagogues: mechanisms, clinical implications, and drug interactions. Journal of diabetes and its complications. 2003. Gribble Fiona M, et al. [Article:12623163@PubMed]
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Sulfonylurea sensitivity of adenosine triphosphate-sensitive potassium channels from beta cells and extrapancreatic tissues. Metabolism: clinical and experimental. 2000. Gribble F M, et al. [Article:11078468@PubMed]

LinkOuts

Web Resource:
Wikipedia
DrugBank:
DB01120
ChEBI:
31654
KEGG Drug:
D01599
PubChem Compound:
3475
PubChem Substance:
46505475
Drugs Product Database (DPD):
2248453
ChemSpider:
3356
Therapeutic Targets Database:
DAP000522

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