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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 KeyInChIKey=YASAKCUCGLMORW-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
    N-Despyridinyl rosiglitazoneDetails
    N-Desmethylrosiglitazone
      N-Desmethyl-ortho-hydroxy rosiglitazoneDetails
      ortho-Hydroxyrosiglitazone
        N-Desmethyl-ortho-hydroxy rosiglitazoneDetails
        N-Desmethylrosiglitazone
          N-Desmethyl-para-hydroxy rosiglitazoneDetails
          para-Hydroxyrosiglitazone
            N-Desmethyl-para-hydroxy rosiglitazoneDetails
            N-Desmethyl-ortho-hydroxy rosiglitazone
              N-Desmethyl-ortho-O-sulfate rosiglitazoneDetails
              ortho-Hydroxyrosiglitazone
                ortho-O-Glucuronide rosiglitazoneDetails
                ortho-Hydroxyrosiglitazone
                  ortho-O-Sulfate rosiglitazoneDetails
                  N-Desmethylrosiglitazone
                    N-Desmethyl glucuronide rosiglitazoneDetails
                    para-Hydroxyrosiglitazone
                      para-O-Glucuronide rosiglitazoneDetails
                      para-Hydroxyrosiglitazone
                        para-O-Sulfate rosiglitazoneDetails
                        N-Desmethyl-para-hydroxy rosiglitazone
                          N-Desmethyl para-O-sulfate rosiglitazoneDetails
                          Rosiglitazone
                            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 solubility3.80e-02 g/lALOGPS
                            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 area71.53ChemAxon
                            rotatable bond count7ChemAxon
                            refractivity97.79ChemAxon
                            polarizability37.8ChemAxon
                            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

                            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

                            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

                            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

                            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

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