Drug/Small Molecule:
rosiglitazone

2D structure

Overview

Generic Names: Rosigliazone maleate; Rosiglitazone maleate; rosiglitazone
Trade Names: Avandia; Rosiglizole
Brand Mixtures: Avandamet (Metformin hydrochloride + Rosiglitazone maleate); Avandaryl (Glimepiride + Rosiglitazone maleate)
PharmGKB Accession Id: PA451283

Description

Rosiglitazone is an anti-diabetic drug in the thiazolidinedione class of drugs. It is marketed by the pharmaceutical company GlaxoSmithKline as a stand-alone drug (Avandia) and in combination with metformin (Avandamet) or with glimepiride (Avandaryl).
Like other thiazolidinediones, the mechanism of action of rosiglitazone is by activation of the intracellular receptor class of the peroxisome proliferator-activated receptors (PPARs), specifically PPARγ. Rosiglitazone is a selective ligand of PPARγ, and has no PPARα-binding action.
Apart from its effect on insulin resistance, it appears to have an anti-inflammatory effect: nuclear factor kappa-B (NFκB) levels fall and inhibitor (IκB) levels increase in patients on rosiglitazone.
Recent research has suggested that rosiglitazone may also be of benefit to a subset of patients with Alzheimer's disease not expressing the ApoE4 allele. This is the subject of a clinical trial currently underway. (source: Drug Bank)

Indication

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

ATC Therapeutic Category

  • A10BG:Thiazolidinediones

Pharmacology, Interactions, and Contraindications

Mechanism Of Action

Rosiglitazone acts as an agonist at peroxisome proliferator activated receptors (PPAR) in target tissues for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPAR-gamma receptors regulates the transcription of insulin-responsive genes involved in the control of glucose production, transport, and utilization. In this way, rosiglitazone enhances tissue sensitivity to insulin. (source: Drug Bank)

Pharmacology

Rosiglitazone, a member of the drug group known as the thiazolidinediones or "insulin sensitizers", is not chemically or functionally related to the alpha-glucosidase inhibitors, the biguanides, or the sulfonylureas. Rosiglitazone targets insulin resistance and, hence, is used alone or with metformine or sulfonylurea to improve glycemic control in patients with type 2 diabetes mellitus. (source: Drug Bank)

Absorption, Distribution, Metabolism, Elimination & Toxicity

Biotransformation

Hepatic. Rosiglitazone is extensively metabolized in the liver to inactive metabolites via N-demethylation, hydroxylation, and conjugation with sulfate and glucuronic acid. In vitro data have shown that Cytochrome (CYP) P450 isoenzyme 2C8 (CYP2C8) and to a minor extent CYP2C9 are involved in the hepatic metabolism of rosiglitazone. (source: Drug Bank)

Protein Binding

99.8% bound to plasma proteins, primarily albumin. (source: Drug Bank)

Absorption

The absolute bioavailability of rosiglitazone is 99%. Peak plasma concentrations are observed about 1 hour after dosing. Administration of rosiglitazone with food resulted in no change in overall exposure (AUC), but there was an approximately 28% decrease in C<sub>max</sub> and a delay in T<sub>max</sub> (1.75 hours). These changes are not likely to be clinically significant; therefore, rosiglitazone may be administered with or without food. (source: Drug Bank)

Toxicity

Side effects include fluid retention, congestive heart failure (CHF), liver disease (source: Drug Bank)

Isomeric SMILES Code:

CN(CCOC1=CC=C(C=C1)C[C@@H]2C(=O)NC(=O)S2)C3=CC=CC=N3 (source: Drug Bank)

Curated Annotations (Curated Annotation)

  1. rs10192566 at chr2:11807879 in LPIN1
    A study in patients with type 2 diabetes treated with rosiglitazone showed that this SNP in the LPIN1 gene was significantly associated with rosiglitazone treatment response. rs11693809 and rs2278513 are in nearly complete linkage disequilibrium with rs10192566.
    Related Drugs:
    rosiglitazone
    Related Diseases:
    Diabetes Mellitus, Type 2
    Evidence:
    PMID:18693052
  2. 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
  3. 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
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
No phenotype data Genotype Data Available Literature annotations available Not annotated
ABCA1
  • CO
  • PD
  •   
  •   
  • GN
Publications
Phenotype data available Genotype Data Available Literature annotations available Has annotations
ABCB1
  •   
  •   
  • PK
  • FA
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
ADIPOQ
  • CO
  • PD
  •   
  •   
  • GN
Publications
Phenotype data available No genotype data Literature annotations available Not annotated
AKT1
  •   
  • PD
  •   
  • FA
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
APOE
  •   
  • PD
  •   
  •   
  • GN
Publications
Phenotype data available Genotype Data Available Literature annotations available Not annotated
CYP2C8
  •   
  • PD
  • PK
  • FA
  • GN
Publications, Variants
Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP2C9
  •   
  •   
  • PK
  •   
  •   
Publications
Phenotype data available No genotype data Literature annotations available Not annotated
FRAP1
  •   
  • PD
  •   
  • FA
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
GSK3B
  •   
  • PD
  •   
  • FA
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
HBA1
  •   
  • PD
  •   
  •   
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
LPIN1
  • CO
  • PD
  •   
  •   
  • GN
Publications, Variants
No phenotype data No genotype data Literature annotations available Not annotated
MMP9
  •   
  • PD
  •   
  • FA
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
NAMPT
  •   
  • PD
  •   
  •   
  •   
Publications
Phenotype data available Genotype Data Available Literature annotations available Has annotations
NR1I2
  •   
  •   
  •   
  • FA
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
PLIN
  • CO
  • PD
  •   
  •   
  • GN
Publications
No phenotype data Genotype Data Available Literature annotations available Not annotated
PPARG
  • CO
  • PD
  •   
  •   
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
PRKAA1
  •   
  • PD
  •   
  • FA
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
PRKAA2
  •   
  • PD
  •   
  • FA
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
PRKAB1
  •   
  • PD
  •   
  • FA
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
PRKAB2
  •   
  • PD
  •   
  • FA
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
PRKAG1
  •   
  • PD
  •   
  • FA
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
PRKAG2
  •   
  • PD
  •   
  • FA
  •   
Publications
Phenotype data available No genotype data Literature annotations available Not annotated
PTEN
  •   
  • PD
  •   
  • FA
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
RBP4
  •   
  • PD
  •   
  •   
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
RPS6KB1
  •   
  • PD
  •   
  • FA
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
SAA1
  •   
  • PD
  •   
  •   
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
SAA2
  •   
  • PD
  •   
  •   
  •   
Publications
No phenotype data Genotype Data Available Literature annotations available Has annotations
SLCO1B1
  •   
  •   
  • PK
  • FA
  • GN
Publications

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

Drug Targets

Gene Description
PPARG Uncurated Annotation (source: Drug Bank)

BioCarta Pathways

External pathways not curated by PharmGKB.

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

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
Alzheimer Disease
  •   
  • PD
  •   
  •   
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Diabetes Mellitus
  •   
  • PD
  •   
  •   
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
diabetes mellitus type 2 and obesity
  •   
  • PD
  •   
  •   
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Diabetes Mellitus, Type 2
  • CO
  • PD
  • PK
  • FA
  • GN
Publications, Variants
No phenotype data No genotype data Literature annotations available Not annotated
HIV
  •   
  • PD
  •   
  •   
  •   
Publications
Phenotype data available Genotype Data Available Literature annotations available Not annotated
Myocardial Infarction
  •   
  •   
  • PK
  •   
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Obesity
  •   
  • PD
  •   
  •   
  •   
Publications

Non-Curated Information

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

LinkOuts

Web Resource:
Wikipedia
DrugBank:
DB00412
KEGG Drug ID:
D00596
PubChem Compound ID:
77999
PubChem Substance ID:
7980539
IUPHAR Ligand ID:
1056

Common Searches

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Non-Curated Publications

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

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