Drug/Small Molecule:

rosiglitazone

Overview

Generic Names:	Rosigliazone maleate; Rosiglitazone maleate; rosiglitazone
IUPAC Name:	5-[[4-[2-(methyl-pyridin-2-ylamino)ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione
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.

Indication

For the treatment of Type II diabetes mellitus

ATC Therapeutic Category

• A10BG:Thiazolidinediones

Pharmacology and Interactions

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.

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.

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.

Protein Binding

99.8% bound to plasma proteins, primarily albumin.

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_max and a delay in T_max (1.75 hours). These changes are not likely to be clinically significant; therefore, rosiglitazone may be administered with or without food.

Half Life

3-4 hours

Toxicity

Side effects include fluid retention, congestive heart failure (CHF), liver disease

Chemical Properties

Chemical Formula:

C₁₈H₁₉N₃O₃S

SMILES Code:

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

(Format: OpenEye Isomeric)

Molecular Weight ( average / monoisotopic )

357.427 / 357.1147

Curated Annotations ()

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 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: 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
   

Curated Information

The following genes are in curated knowledge about this drug.

	Gene	Relationship	Evidence
	ADIPOQ	PD       GN	Publications
	APOE	PD       GN	Publications
	CYP2C8	PD PK    GN	Publications, Variants
	CYP2C9	PK	Publications
	HBA1	PD       GN	Publications
	LPIN1		Variants
	NAMPT	PD	Publications
	NR1I2	FA	Publications
	PPARG	PD       GN	Publications
	RBP4	PD	Publications
	SAA1	PD	Publications
	SAA2	PD	Publications
	SLCO1B1	PK FA GN	Publications

Non-Curated Information

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

Metabolizing Enzymes

• CYP2C9
• CYP2C8

Drug Targets

• PPARG

BioCarta Pathways†

• visceral fat deposits and the metabolic syndrome - (BioCarta via Pathway Interaction Database)

Non-Curated Information

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
	Alzheimer Disease	PD       GN	Publications
	Diabetes Mellitus	PD       GN	Publications
	diabetes mellitus type 2 and obesity	PD       GN	Publications
	Diabetes Mellitus, Type 2	PD       GN	Publications, Variants
	HIV	PD	Publications
	Myocardial Infarction	PK    GN	Publications
	Obesity	PD	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.