PharmGKB: The Pharmacogenomics Knowledge Base

Drug/Small Molecule:
repaglinide

2D structure

Overview

Generic Names: AG-EE 388 ZW; AG-EE 623 ZW; Repaglinida [INN-Spanish]; Repaglinidum [INN-Latin]; repaglinide
Trade Names: Prandin
PharmGKB Accession Id: PA451234

Description

Repaglinide is a blood-glucose lowering drug. It lowers blood glucose by stimulating the release of insulin from the pancreas. It achieves this by closing ATP-dependent potassium channels in the membrane of the beta cells. This depolarizes the beta cells, opening the cells' calcium channels, and the resulting calcium influx induces insulin secretion. (source: Drug Bank)

Indication

For the treatment of Type II diabetes mellitus. (source: Drug Bank)

ATC Therapeutic Category

  • A10BX:Other blood glucose lowering drugs, excl. insulins

Pharmacology, Interactions, and Contraindications

Mechanism Of Action

Repaglinide closes ATP-dependent potassium channels in the b-cell membrane by binding at characterizable sites. This potassium channel blockade depolarizes the b-cell, which leads to an opening of calcium channels. The resulting increased calcium influx induces insulin secretion. The ion channel mechanism is highly tissue selective with low affinity for heart and skeletal muscle. (source: Drug Bank)

Pharmacology

Repaglinide is an oral blood glucose-lowering drug of the meglitinide class used in the management of type 2 diabetes mellitus (also known as non-insulin dependent diabetes mellitus or NIDDM). Repaglinide lowers blood glucose levels by stimulating the release of insulin from the pancreas. This action is dependent upon functioning beta cells in the pancreatic islets. Insulin release is glucose-dependent and diminishes at low glucose concentrations. (source: Drug Bank)

Food Interactions

Take upto 30 minutes before meals. (source: Drug Bank)

Absorption, Distribution, Metabolism, Elimination & Toxicity

Biotransformation

Repaglinide is completely metabolized by oxidative biotransformation and direct conjugation with glucuronic acid after either an IV or oral dose. (source: Drug Bank)

Protein Binding

>98% (source: Drug Bank)

Absorption

Rapid (bioavailability is 56%) (source: Drug Bank)

Toxicity

LD<sub>50</sub> >1 g/kg (rat) (W. Grell) (source: Drug Bank)

Isomeric SMILES Code:

CCOc1cc(ccc1C(=O)O)CC(=O)N[C@@H](CC(C)C)c2ccccc2N3CCCCC3 (source: Drug Bank)

Curated Annotations (Curated Annotation)

  1. rs10509681 at chr10:96788739 in CYP2C8
    Different literature sources show a discrepancy between several in vitro findings describing a lower activity of the CYP2C8*3 variant and in vivo findings showing higher oral clearance in *3 allele carriers at least for some substrates of CYP2C8. A study on healthy volunteers administered with repaglinide found that the CYP2C8*3 variant allele was associated with reduced plasma concentrations of repaglinide. Another study showed that subjects carrying the CYP2C8*3 allele had a lower rosiglitazone plasma concentration.
    Variant Name:
    CYP2C8: K399R; A1196G; CYP2C8*3
    Related Drugs:
    repaglinide, rosiglitazone
    Evidence:
    PMID:14534525
    PMID:17178266
  2. rs11572080 at chr10:96817020 in CYP2C8
    Different literature sources show a discrepancy between several in vitro findings describing a lower activity of the CYP2C8*3 variant and in vivo findings showing higher oral clearance in *3 allele carriers at last for some substrates ofCYP2C8. A study on healthy volunteers administered with repaglinide found that the CYP2C8*3 variant allele was associated with reduced plasma conentrations of repaglinde. Another study showed that subjects carrying the CYP2C8*3allele had a lower rosiglitazone plasma concentartion.
    Variant Name:
    CYP2C8: R139K; G416A; CYP2C8*3
    Related Drugs:
    repaglinide, rosiglitazone
    Evidence:
    PMID:14534525
    PMID:17178266
  3. rs290487 at chr10:114899721 in TCF7L2
    Risk or phenotype-associated allele: T allele. Phenotype: Body mass index was significantly lower (p < 0.030), and cholesterol levels (p < 0.012)) were significantly higher in T2DM patients with the T allele in a comparison of the TT, TC, and CC genotypes. Study size: 259. Study population/ethnicity: Chinese type 2 Diabetes (T2DM) patients. Significance metric(s): p < 0.03. Type of association: GN
    Variant Name:
    TCF7L2: intronic C>T SNP
    Related Drugs:
    repaglinide
    Related Diseases:
    Diabetes Mellitus, Type 2
    Evidence:
    PMID:20054294
  4. rs290487 at chr10:114899721 in TCF7L2
    Risk or phenotype-associated allele: TT genotype. Phenotype: After 8-week repaglinide treatment, fasting insulin, triglycerides, and low-density lipoprotein cholesterol (LDL-c) were significantly increased in T2DM patients with the TT genotype (n = 14) compared to patients with the CC and TC genotypes combined (n = 26) (p < 0.043), meaning that TT subjects showed improved repaglinide efficacy compared to subjects with the TC and CC genotypes. Study Size: 40. Study population/ethnicity: Chinese type 2 Diabetes (T2DM) patients with uniform genotype with regard to SLCO1B3 (OATP1B1) T521C. Significance metric(s): p < 0.043. Type of association: GN; PD
    Variant Name:
    TCF7L2: intronic C>T SNP
    Related Drugs:
    repaglinide
    Related Diseases:
    Diabetes Mellitus, Type 2
    Evidence:
    PMID:20054294
  5. rs5219 at chr11:17366148 in KCNJ11
    Risk or phenotype-associated allele: G allele. Phenotype: Increased levels of fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) (p < 0.05); and post-repaglinide treatment, GA or AA genotype carries had increased levels of FPG, PPG, and glycated hemoglobin (HbA(1c)) compared with patients with the GG genotype (p < 0.05) Study size: 259 type II diabetes cases and 188 healthy controls. Study population/ethnicity: Chinese. Significance metric(s): p < 0.05. Type of association: GN; PD.
    Variant Name:
    KCNJ11: Lys23Glu
    Related Drugs:
    repaglinide
    Related Diseases:
    Diabetes Mellitus, Type 2
    Evidence:
    PMID:20054294
  6. rs5219 at chr11:17366148 in KCNJ11
    Risk or phenotype-associated allele: GG (23Glu/Glu) genotype. Phenotype: After 8-week repaglinide treatment, levels of fasting plasma glucose, postprandial plasma glucose, and percent HbA(1c) glycated hemoglobin were significantly lower in T2DM patients with the GG (23Glu/Glu) genotype (n = 18) compared to patients with the AA (23Lys/Lys) and AG (23Lys/Glu) genotypes combined (n = 22) (p < 0.036). Study Size: 40. Study population/ethnicity: Chinese type 2 Diabetes (T2DM) patients with uniform genotype with regard to SLCO1B3 (OATP1B1) T521C. Significance metric(s): p < 0.036. Type of association: GN; PD.
    Variant Name:
    KCNJ11:67A>G, Lys23Glu (E23K)
    Related Drugs:
    repaglinide
    Related Diseases:
    Diabetes Mellitus, Type 2
    Evidence:
    PMID:20054294
  7. rs2306283 at chr12:21221005 in SLCO1B1
    Homozygosity for the G allele of this SNP was associated with reduced plasma concentrations of repaglinide, but not nateglinide, in healthy volunteers dosed separately with each of these drugs.
    Variant Name:
    SLC01B1*1B, SLCO1B1:N130D
    Related Drugs:
    nateglinide, repaglinide
    Evidence:
    PMID:18854776
  8. rs4149056 at chr12:21222816 in SLCO1B1
    Variant with C allele showed increased plasma AUC of repaglinide relative to T
    Variant Name:
    SLCO1B1:521T>C, SLCO1B1:*5
    Related Drugs:
    repaglinide
    Evidence:
    PMID:18187595
Variant names are different names that have been used in the literature and other resources to refer to the same variant.

The following genes are in curated knowledge about this drug.

  Gene Relationship Evidence
Phenotype data available Genotype Data Available Literature annotations available Not annotated
CYP2C8
  •   
  • PD
  • PK
  •   
  • GN
Publications, Variants
Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP3A4
  •   
  •   
  • PK
  •   
  •   
Publications
No phenotype data Genotype Data Available Literature annotations available Has annotations
KCNJ11
  •   
  • PD
  • PK
  •   
  •   
Publications, Variants
No phenotype data Genotype Data Available Literature annotations available Has annotations
SLCO1B1
  •   
  •   
  • PK
  • FA
  • GN
Publications, Variants
No phenotype data No genotype data Literature annotations available Not annotated
TCF7L2
  •   
  • PD
  • PK
  •   
  •   
Publications, Variants

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

Drug Targets

Gene Description
ABCC8 Uncurated Annotation (source: Drug Bank)
KCNJ1 Uncurated Annotation (source: Drug Bank)
KCNJ11 Uncurated Annotation (source: Drug Bank)

The following drugs are in curated knowledge about this drug.

  Drug Relationship Evidence
No phenotype data No genotype data Literature annotations available Not annotated
gemfibrozil
  •   
  •   
  • PK
  •   
  •   
Publications

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

Drug Interactions

Drug Description
acebutolol Uncurated Annotation The beta-blocker decreases the symptoms of hypoglycemia (source: Drug Bank)
atenolol Uncurated Annotation The beta-blocker decreases the symptoms of hypoglycemia (source: Drug Bank)
betaxolol Uncurated Annotation The beta-blocker decreases the symptoms of hypoglycemia (source: Drug Bank)
bisoprolol Uncurated Annotation The beta-blocker decreases the symptoms of hypoglycemia (source: Drug Bank)
carvedilol Uncurated Annotation The beta-blocker decreases the symptoms of hypoglycemia (source: Drug Bank)
chlorpropamide Uncurated Annotation Similar mode of action - questionable association (source: Drug Bank)
clarithromycin Uncurated Annotation Clarithromycin increases the effect of repaglinide (source: Drug Bank)
cyclosporine Uncurated Annotation Cyclosporine increases the effect of repaglinide (source: Drug Bank)
erythromycin Uncurated Annotation The macrolide increases the effect of repaglinide (source: Drug Bank)
esmolol Uncurated Annotation The beta-blocker decreases the symptoms of hypoglycemia (source: Drug Bank)
gemfibrozil Uncurated Annotation Gemfibrozil increases the effect and toxicity of repaglinide (source: Drug Bank)
glibenclamide Uncurated Annotation Similar mode of action - questionable association (source: Drug Bank)
gliclazide Uncurated Annotation Similar mode of action - questionable association (source: Drug Bank)
glimepiride Uncurated Annotation Similar mode of action - questionable association (source: Drug Bank)
glipizide Uncurated Annotation Similar mode of action - questionable association (source: Drug Bank)
metoprolol Uncurated Annotation The beta-blocker decreases the symptoms of hypoglycemia (source: Drug Bank)
nadolol Uncurated Annotation The beta-blocker decreases the symptoms of hypoglycemia (source: Drug Bank)
oxprenolol Uncurated Annotation The beta-blocker decreases the symptoms of hypoglycemia (source: Drug Bank)
pindolol Uncurated Annotation The beta-blocker decreases the symptoms of hypoglycemia (source: Drug Bank)
propranolol Uncurated Annotation The beta-blocker decreases the symptoms of hypoglycemia (source: Drug Bank)
rifampin Uncurated Annotation Rifampin decreases the effect of repaglinide (source: Drug Bank)
sotalol Uncurated Annotation The beta-blocker decreases the symptoms of hypoglycemia (source: Drug Bank)
timolol Uncurated Annotation The beta-blocker decreases the symptoms of hypoglycemia (source: Drug Bank)
tolbutamide Uncurated Annotation Similar mode of action - questionable association (source: Drug Bank)

Curated Information

The following diseases are in curated knowledge about this drug.

  Disease Relationship Evidence
No phenotype data No genotype data Literature annotations available Not annotated
Diabetes Mellitus
  •   
  •   
  • PK
  •   
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Diabetes Mellitus, Type 2
  •   
  • PD
  • PK
  •   
  •   
Publications, Variants

Non-Curated Information

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

LinkOuts

Web Resource:
Wikipedia
DrugBank:
DB00912
KEGG Compound ID:
C07670
KEGG Drug ID:
D00594
PubChem Compound ID:
65981
PubChem Substance ID:
208038

Common Searches

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Non-Curated Publications

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

PharmGKB integrates drug information from different sources: DrugBank, Open Eye Scientific Software.
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