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Identification
NameRosiglitazone
Accession NumberDB00412  (APRD00403)
TypeSmall Molecule
GroupsApproved, Investigational
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.

Structure
Thumb
Synonyms
SynonymLanguageCode
(±)-5-[p-[2-(methyl-2-pyridylamino)ethoxy]benzyl]-2,4-thiazolidinedioneNot AvailableWHO
(RS)-5-{4-[2-(Methyl-2-pyridylamino)ethoxy]benzyl}-2,4-thiazolidinedionNot AvailableIUPAC
RosiglitazonGermanINN
RosiglitazonaSpanishINN
RosiglitazoneNot Available DCF, BAN
RosiglitazonumLatinINN
Salts
Name/CAS Structure Properties
Rosiglitazone Maleate
155141-29-0
Thumb
  • InChI Key: SUFUKZSWUHZXAV-BTJKTKAUNA-N
  • Monoisotopic Mass: 473.125670795
  • Average Mass: 473.499
DBSALT000153
Brand names
NameCompany
AvandiaGlaxoSmithKline
BlutabWerrick
DH-RosidiaHasan
DiabenElea
DiaglinexFarmindustria
GaudilCraveri
GliximinaDenver
NaidiHisun
RogelinTorrent
RoglitGedeon Richter
RomerolDrug International
RositDelta
RosixGarmisch
RossiniTrima
SensulinSquare
Sheng AoHengrui
Sheng MinShengJiTang Pharmaceutical
Brand mixtures
Brand NameIngredients
ArometRosiglitazone and Metformin
AvaglimRosiglitazone and Glimepiride
AvandametRosiglitazone and Metformin
AvandarylRosiglitazone and Glimepiride
AvglimRosiglitazone and Glimepiride
GlyrosRosiglitazone and Glimepiride
Grexa PlusRosiglitazone and Glimepiride
MetiglitRosiglitazone and Metformin
Oramet PlusRosiglitazone and Metformin
Rogelin 2MF/4MFRosiglitazone and Metformin
RoglimRosiglitazone and Glimepiride
RosiglimRosiglitazone and Glimepiride
RosimetRosiglitazone and Metformin
RotaminRosiglitazone and Metformin
CategoriesNot Available
CAS number122320-73-4
WeightAverage: 357.427
Monoisotopic: 357.114712179
Chemical FormulaC18H19N3O3S
InChI KeyYASAKCUCGLMORW-UHFFFAOYNA-N
InChI
InChI=1/C18H19N3O3S/c1-21(16-4-2-3-9-19-16)10-11-24-14-7-5-13(6-8-14)12-15-17(22)20-18(23)25-15/h2-9,15H,10-12H2,1H3,(H,20,22,23)
IUPAC Name
5-[(4-{2-[methyl(pyridin-2-yl)amino]ethoxy}phenyl)methyl]-1,3-thiazolidine-2,4-dione
SMILES
CN(CCOC1=CC=C(CC2SC(=O)NC2=O)C=C1)C1=CC=CC=N1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassBenzene and Substituted Derivatives
SubclassPhenol Ethers
Direct parentPhenol Ethers
Alternative parentsThiazolidinediones; Aminopyridines and Derivatives; Alkyl Aryl Ethers; N-unsubstituted Carboxylic Acid Imides; Secondary Carboxylic Acid Amides; Tertiary Amines; Carboxylic Acids; Polyamines
Substituentsalkyl aryl ether; aminopyridine; thiazolidinedione; pyridine; thiazolidinone; thiazolidine; carboxylic acid imide, n-unsubstituted; secondary carboxylic acid amide; carboxamide group; tertiary amine; ether; carboxylic acid derivative; carboxylic acid; polyamine; amine; organonitrogen compound
Classification descriptionThis compound belongs to the phenol ethers. These are aromatic compounds containing an ether group substituted with a benzene ring.
Pharmacology
IndicationRosiglitazone is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
PharmacodynamicsWhen rosiglitazone is used as monotherapy, it is associated with increases in total cholesterol, LDL, and HDL. It is also associated with decreases in free fatty acids. Increases in LDL occurred primarily during the first 1 to 2 months of therapy with AVANDIA and LDL levels remained elevated above baseline throughout the trials. In contrast, HDL continued to rise over time. As a result, the LDL/HDL ratio peaked after 2 months of therapy and then appeared to decrease over time.
Mechanism of actionRosiglitazone acts as a highly selective and potent 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.
AbsorptionThe 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 Cmax and a delay in Tmax (1.75 hours). These changes are not likely to be clinically significant; therefore, rosiglitazone may be administered with or without food. Maximum plasma concentration (Cmax) and the area under the curve (AUC) of rosiglitazone increase in a dose-proportional manner over the therapeutic dose range.
Volume of distribution
  • 17.6 L [oral volume of distribution Vss/F]
  • 13.5 L [population mean, pediatric patients]
Protein binding99.8% bound to plasma proteins, primarily albumin.
Metabolism

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.

SubstrateEnzymesProduct
Rosiglitazone
N-DesmethylrosiglitazoneDetails
Rosiglitazone
para-HydroxyrosiglitazoneDetails
Rosiglitazone
ortho-HydroxyrosiglitazoneDetails
Rosiglitazone
Not Available
N-Despyridinyl rosiglitazoneDetails
N-Desmethylrosiglitazone
Not Available
N-Desmethyl-ortho-hydroxy rosiglitazoneDetails
ortho-Hydroxyrosiglitazone
Not Available
N-Desmethyl-ortho-hydroxy rosiglitazoneDetails
N-Desmethylrosiglitazone
Not Available
N-Desmethyl-para-hydroxy rosiglitazoneDetails
para-Hydroxyrosiglitazone
Not Available
N-Desmethyl-para-hydroxy rosiglitazoneDetails
N-Desmethyl-ortho-hydroxy rosiglitazone
Not Available
N-Desmethyl-ortho-O-sulfate rosiglitazoneDetails
ortho-Hydroxyrosiglitazone
Not Available
ortho-O-Glucuronide rosiglitazoneDetails
ortho-Hydroxyrosiglitazone
Not Available
ortho-O-Sulfate rosiglitazoneDetails
N-Desmethylrosiglitazone
Not Available
N-Desmethyl glucuronide rosiglitazoneDetails
para-Hydroxyrosiglitazone
Not Available
para-O-Glucuronide rosiglitazoneDetails
para-Hydroxyrosiglitazone
Not Available
para-O-Sulfate rosiglitazoneDetails
N-Desmethyl-para-hydroxy rosiglitazone
Not Available
N-Desmethyl para-O-sulfate rosiglitazoneDetails
Rosiglitazone
Not Available
Phenoxyacetic acid derivative of rosiglitazoneDetails
Route of eliminationFollowing oral or intravenous administration of [14C]rosiglitazone maleate, approximately 64% and 23% of the dose was eliminated in the urine and in the feces, respectively.
Half life3-4 hours (single oral dose, independent of dose)
Clearance
  • Oral clearance (CL) = 3.03 ± 0.87 L/hr [1 mg Fasting]
  • Oral CL = 2.89 ± 0.71 L/hr [2 mg Fasting]
  • Oral CL = 2.85 ± 0.69 L/hr [8 mg Fasting]
  • Oral CL = 2.97 ± 0.81 L/hr [8 mg Fed]
  • 3.15 L/hr [Population mean, Pediatric patients]
ToxicitySide effects include fluid retention, congestive heart failure (CHF), liver disease
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9861
Blood Brain Barrier + 0.8994
Caco-2 permeable - 0.5451
P-glycoprotein substrate Substrate 0.6535
P-glycoprotein inhibitor I Non-inhibitor 0.5274
P-glycoprotein inhibitor II Non-inhibitor 0.6289
Renal organic cation transporter Non-inhibitor 0.5203
CYP450 2C9 substrate Non-substrate 0.7418
CYP450 2D6 substrate Non-substrate 0.9116
CYP450 3A4 substrate Substrate 0.5744
CYP450 1A2 substrate Inhibitor 0.5391
CYP450 2C9 substrate Inhibitor 0.5783
CYP450 2D6 substrate Non-inhibitor 0.846
CYP450 2C19 substrate Inhibitor 0.5884
CYP450 3A4 substrate Non-inhibitor 0.8309
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.7213
Ames test Non AMES toxic 0.687
Carcinogenicity Non-carcinogens 0.9465
Biodegradation Not ready biodegradable 0.8635
Rat acute toxicity 2.4515 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.8055
hERG inhibition (predictor II) Non-inhibitor 0.7768
Pharmacoeconomics
Manufacturers
  • Sb pharmco puerto rico inc
  • GlaxoSmithKline
Packagers
Dosage forms
FormRouteStrength
TabletOral2 mg, 4 mg, 8 mg
Prices
Unit descriptionCostUnit
Avandia 8 mg tablet8.69USDtablet
Avandia 4 mg tablet4.72USDtablet
Avandia 2 mg tablet3.22USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States73583662000-10-192020-10-19
United States50029531994-09-172011-09-17
Canada21438492000-04-252013-09-01
Canada13284521994-04-122011-04-12
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point122-123 °CNot Available
logP2.4Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.038ALOGPS
logP2.95ALOGPS
logP2.45ChemAxon
logS-4ALOGPS
pKa (Strongest Acidic)6.84ChemAxon
pKa (Strongest Basic)6.23ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area71.53 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity97.79 m3·mol-1ChemAxon
Polarizability37.8 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Manne Reddy, “Amorphous form of rosiglitazone maleate and process for preparation thereof.” U.S. Patent US20040242658, issued December 02, 2004.

US20040242658
General Reference
  1. Mohanty P, Aljada A, Ghanim H, Hofmeyer D, Tripathy D, Syed T, Al-Haddad W, Dhindsa S, Dandona P: Evidence for a potent antiinflammatory effect of rosiglitazone. J Clin Endocrinol Metab. 2004 Jun;89(6):2728-35. Pubmed
  2. Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, Kravitz BG, Lachin JM, O’Neill MC, Zinman B, Viberti G: Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006 Dec 7;355(23):2427-43. Epub 2006 Dec 4. Pubmed
External Links
ResourceLink
KEGG DrugD00596
BindingDB28681
ChEBI50122
ChEMBLCHEMBL121
Therapeutic Targets DatabaseDAP000271
PharmGKBPA451283
IUPHAR1056
Guide to Pharmacology1056
HETBRL
Drug Product Database2241113
RxListhttp://www.rxlist.com/cgi/generic2/rosigl.htm
Drugs.comhttp://www.drugs.com/cdi/rosiglitazone.html
PDRhealthhttp://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/cx1532.shtml
WikipediaRosiglitazone
ATC CodesA10BG02
AHFS Codes
  • 68:20.28
PDB EntriesNot Available
FDA labelshow(86.2 KB)
MSDSshow(30 KB)
Interactions
Drug Interactions
Drug
AvanafilCo-administration with avanafil resulted in an approximate 2.0% increase in AUC0-inf and 14% decrease in Cmax of rosiglitazone.
ColesevelamBile Acid Sequestrants may decrease the absorption of Antidiabetic Agents (Thiazolidinedione). Separate the dosing of bile acid sequestrants and thiazolidinediones by at least 2 hours. Monitor for reduced effects of the antidiabetic agents.
GemfibrozilIncreases the effect and toxicity of rosiglitazone/pioglitazone
KetoconazoleKetoconazole increases the effect of rosiglitazone
RifampicinRifampin reduces levels and efficacy of rosiglitazone
Somatropin recombinantSomatropin may antagonize the hypoglycemic effect of rosiglitazone. Monitor for changes in fasting and postprandial blood sugars.
TretinoinThe moderate CYP2C8 inhibitor, Rosiglitazone, may decrease the metabolism and clearance of oral Tretinoin. Monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Rosiglitazone is initiated, discontinued to dose changed.
Food InteractionsNot Available

Targets

1. Peroxisome proliferator-activated receptor gamma

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: agonist

Components

Name UniProt ID Details
Peroxisome proliferator-activated receptor gamma P37231 Details

References:

  1. Su JL, Winegar DA, Wisely GB, Sigel CS, Hull-Ryde EA: Use of a PPAR gamma-specific monoclonal antibody to demonstrate thiazolidinediones induce PPAR gamma receptor expression in vitro. Hybridoma. 1999 Jun;18(3):273-80. Pubmed
  2. Rieusset J, Auwerx J, Vidal H: Regulation of gene expression by activation of the peroxisome proliferator-activated receptor gamma with rosiglitazone (BRL 49653) in human adipocytes. Biochem Biophys Res Commun. 1999 Nov;265(1):265-71. Pubmed
  3. Kameda N, Okuya S, Oka Y: [Rosiglitazone (BRL-49653)] Nippon Rinsho. 2000 Feb;58(2):401-4. Pubmed
  4. Johnson BA, Wilson EM, Li Y, Moller DE, Smith RG, Zhou G: Ligand-induced stabilization of PPARgamma monitored by NMR spectroscopy: implications for nuclear receptor activation. J Mol Biol. 2000 Apr 28;298(2):187-94. Pubmed
  5. Camp HS, Li O, Wise SC, Hong YH, Frankowski CL, Shen X, Vanbogelen R, Leff T: Differential activation of peroxisome proliferator-activated receptor-gamma by troglitazone and rosiglitazone. Diabetes. 2000 Apr;49(4):539-47. Pubmed
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. Long-chain-fatty-acid--CoA ligase 4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Long-chain-fatty-acid--CoA ligase 4 O60488 Details

References:

  1. Askari B, Kanter JE, Sherrid AM, Golej DL, Bender AT, Liu J, Hsueh WA, Beavo JA, Coleman RA, Bornfeldt KE: Rosiglitazone inhibits acyl-CoA synthetase activity and fatty acid partitioning to diacylglycerol and triacylglycerol via a peroxisome proliferator-activated receptor-gamma-independent mechanism in human arterial smooth muscle cells and macrophages. Diabetes. 2007 Apr;56(4):1143-52. Epub 2007 Jan 26. Pubmed

Enzymes

1. Cytochrome P450 2C8

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2C8 P10632 Details

References:

  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

2. Cytochrome P450 2C9

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2C9 P11712 Details

References:

  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

3. Prostaglandin G/H synthase 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Prostaglandin G/H synthase 1 P23219 Details

References:

  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed

4. Cytochrome P450 1A2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 1A2 P05177 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

5. Cytochrome P450 2A6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2A6 P11509 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

6. Cytochrome P450 2C19

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2C19 P33261 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

7. Cytochrome P450 2D6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2D6 P10635 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

Carriers

1. Serum albumin

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Serum albumin P02768 Details

References:

  1. FDA label

Transporters

1. Solute carrier organic anion transporter family member 1B1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Solute carrier organic anion transporter family member 1B1 Q9Y6L6 Details

References:

  1. Nozawa T, Sugiura S, Nakajima M, Goto A, Yokoi T, Nezu J, Tsuji A, Tamai I: Involvement of organic anion transporting polypeptides in the transport of troglitazone sulfate: implications for understanding troglitazone hepatotoxicity. Drug Metab Dispos. 2004 Mar;32(3):291-4. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on November 29, 2013 14:37