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Showing drug card for Rosiglitazone (DB00412)

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Version 2.5
Creation Date 2005-06-13 13:24:05
Update Date 2009-02-19 16:05:06
Primary Accession Number DB00412
Secondary Accession Number
  • APRD00403
Name Rosiglitazone
Drug Type
  • Approved
  • Investigational
  • Small Molecule
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.
Synonyms
  1. Rosigliazone maleate
  2. Rosiglitazone maleate
  3. rosiglitazone
Brand Names
  1. Avandia
  2. Rosiglizole
Brand Mixtures
  1. Avandamet (Metformin hydrochloride + Rosiglitazone maleate)
  2. Avandaryl (Glimepiride + Rosiglitazone maleate)
Chemical IUPAC Name 5-[[4-[2-(methyl-pyridin-2-ylamino)ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione
Chemical Formula C18H19N3O3S
Chemical Structure Structure
CAS Registry Number 122320-73-4
InChI Identifier 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)/f/h20H
InChI Key YASAKCUCGLMORW-UYBDAZJACF
KEGG Drug D00596 Link Image
KEGG Compound Not Available
PubChem Compound 77999 Link Image
PubChem Substance 7980539 Link Image
ChEBI ID Not Available
PharmGKB ID PA451283 Link Image
HET ID BRL Link Image
GenBank ID Not Available
Drug ID Number [DIN] 02241113 Link Image
RxList Link http://www.rxlist.com/cgi/generic2/rosigl.htm Link Image
PDRhealth Link http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/cx1532.shtml Link Image
Wikipedia Link http://en.wikipedia.org/wiki/Rosiglitazone Link Image
FDA Label
Material Safety Data Sheet (MSDS)
Synthesis Reference Crowther, Smith, U.S. Pat. 3,337,628 (1967)
Average Molecular Weight 357.4270
Monoisotopic Molecular Weight 357.1147
State Solid
Melting Point 122-123 oC
Experimental Water Solubility Not Available Source: PhysProp
Predicted Water Solubility 3.80e-02 mg/mL Calculated using ALOGPS
Experimental LogP/Hydrophobicity 2.4 Source: PhysProp
Predicted LogP 2.95 Calculated using ALOGPS
Experimental LogS Not Available
Predicted LogS -3.97 Calculated using ALOGPS
Experimental Caco2 Permeability Not Available
pKa/Isoelectric Point Not Available
Mass Spectrum Not Available
MOL File Show Link Image | Download Link Image
SDF File Show Link Image | Download Link Image
PDB File Show Link Image | Download Link Image
2D Structure
3D Structure
Experimental PDB ID Not Available
Isomeric SMILES CN(CCOC1=CC=C(C[C@H]2SC(=O)NC2=O)C=C1)C1=CC=CC=N1
Canonical SMILES CN(CCOC1=CC=C(CC2SC(=O)NC2=O)C=C1)C1=CC=CC=N1
Drug Category
  • Fibrinolytic Agents
  • Hypoglycemic Agents
  • Thazolidinediones
  • Vasodilator Agents
ATC Codes
AHFS Codes
  • 68:20.28
Indication For the treatment of Type II diabetes mellitus
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.
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.
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 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.
Toxicity Side effects include fluid retention, congestive heart failure (CHF), liver disease
Protein Binding 99.8% bound to plasma proteins, primarily albumin.
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.
Half Life 3-4 hours
Dosage Forms
Form Route
Tablet Oral
Patient Information Show Link Image
Contraindications Show Link Image
Interactions Show Link Image
Drug Interactions Not Available
Food Interactions Not Available
Pathways Not Available
General References
  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 Link Image]
  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 Link Image]
  3. Drugs.com Link Image
  4. Wikipedia Link Image
  5. RxList Link Image
  6. PDRhealth Link Image
Organisms Affected
  • Humans and other mammals
Phase 1 Metabolizing Enzymes
  1. Cytochrome P450 2C8 (CYP2C8)
  2. Cytochrome P450 2C9 (CYP2C9)
Targets
  1. Peroxisome proliferator-activated receptor gamma
Phase 1 Metabolizing Enzyme 1 [top]
Enzyme 1 Name Cytochrome P450 2C8 (CYP2C8)
Enzyme 1 Gene Name CYP2C8
Enzyme 1 SwissProt ID P10632 Link Image
Enzyme 1 SNPs SNPJam Report Link Image
Enzyme 1 Protein Sequence >sp|P10632|CP2C8_HUMAN Cytochrome P450 2C8 (EC 1.14.14.1) 
MEPFVVLVLCLSFMLLFSLWRQSCRRRKLPPGPTPLPIIGNMLQIDVKDICKSFTNFSKV
YGPVFTVYFGMNPIVVFHGYEAVKEALIDNGEEFSGRGNSPISQRITKGLGIISSNGKRW
KEIRRFSLTTLRNFGMGKRSIEDRVQEEAHCLVEELRKTKASPCDPTFILGCAPCNVICS
VVFQKRFDYKDQNFLTLMKRFNENFRILNSPWIQVCNNFPLLIDCFPGTHNKVLKNVALT
RSYIREKVKEHQASLDVNNPRDFIDCFLIKMEQEKDNQKSEFNIENLVGTVADLFVAGTE
TTSTTLRYGLLLLLKHPEVTAKVQEEIDHVIGRHRSPCMQDRSHMPYTDAVVHEIQRYSD
LVPTGVPHAVTTDTKFRNYLIPKGTTIMALLTSVLHDDKEFPNPNIFDPGHFLDKNGNFK
KSDYFMPFSAGKRICAGEGLARMELFLFLTTILQNFNLKSVDDLKNLNTTAVTKGIVSLP
PSYQICFIPV
Phase 1 Metabolizing Enzyme 2 [top]
Enzyme 2 Name Cytochrome P450 2C9 (CYP2C9)
Enzyme 2 Gene Name CYP2C9
Enzyme 2 SwissProt ID P11712 Link Image
Enzyme 2 SNPs SNPJam Report Link Image
Enzyme 2 Protein Sequence >sp|P11712|CP2C9_HUMAN Cytochrome P450 2C9 (EC 1.14.13.80) 
MDSLVVLVLCLSCLLLLSLWRQSSGRGKLPPGPTPLPVIGNILQIGIKDISKSLTNLSKV
YGPVFTLYFGLKPIVVLHGYEAVKEALIDLGEEFSGRGIFPLAERANRGFGIVFSNGKKW
KEIRRFSLMTLRNFGMGKRSIEDRVQEEARCLVEELRKTKASPCDPTFILGCAPCNVICS
IIFHKRFDYKDQQFLNLMEKLNENIKILSSPWIQICNNFSPIIDYFPGTHNKLLKNVAFM
KSYILEKVKEHQESMDMNNPQDFIDCFLMKMEKEKHNQPSEFTIESLENTAVDLFGAGTE
TTSTTLRYALLLLLKHPEVTAKVQEEIERVIGRNRSPCMQDRSHMPYTDAVVHEVQRYID
LLPTSLPHAVTCDIKFRNYLIPKGTTILISLTSVLHDNKEFPNPEMFDPHHFLDEGGNFK
KSKYFMPFSAGKRICVGEALAGMELFLFLTSILQNFNLKSLVDPKNLDTTPVVNGFASVP
PFYQLCFIPV
Drug Target 1 [top]
Target 1 ID 238
Target 1 Name Peroxisome proliferator-activated receptor gamma
Target 1 Synonyms
  1. PPAR-gamma
Target 1 Gene Name PPARG
Target 1 Protein Sequence >Peroxisome proliferator-activated receptor gamma 
MGETLGDSPIDPESDSFTDTLSANISQEMTMVDTEMPFWPTNFGISSVDLSVMEDHSHSF
DIKPFTTVDFSSISTPHYEDIPFTRTDPVVADYKYDLKLQEYQSAIKVEPASPPYYSEKT
QLYNKPHEEPSNSLMAIECRVCGDKASGFHYGVHACEGCKGFFRRTIRLKLIYDRCDLNC
RIHKKSRNKCQYCRFQKCLAVGMSHNAIRFGRMPQAEKEKLLAEISSDIDQLNPESADLR
ALAKHLYDSYIKSFPLTKAKARAILTGKTTDKSPFVIYDMNSLMMGEDKIKFKHITPLQE
QSKEVAIRIFQGCQFRSVEAVQEITEYAKSIPGFVNLDLNDQVTLLKYGVHEIIYTMLAS
LMNKDGVLISEGQGFMTREFLKSLRKPFGDFMEPKFEFAVKFNALELDDSDLAIFIAVII
LSGDRPGLLNVKPIEDIQDNLLQALELQLKLNHPESSQLFAKLLQKMTDLRQIVTEHVQL
LQVIKKTETDMSLHPLLQEIYKDLY
Target 1 Number of Residues 513
Target 1 Molecular Weight 57621
Target 1 Theoretical pI 5.77
Target 1 GO Classification
Function
steroid hormone receptor activity
transcription factor activity
signal transducer activity
receptor activity
ligand-dependent nuclear receptor activity
binding
nucleic acid binding
DNA binding
Process
regulation of biological process
regulation of physiological process
regulation of metabolism
regulation of cellular metabolism
regulation of nucleobase, nucleoside, nucleotide and nucleic acid metabolism
regulation of transcription
regulation of transcription, DNA-dependent
Component
organelle
membrane-bound organelle
intracellular membrane-bound organelle
nucleus
Target 1 General Function Involved in DNA binding
Target 1 Specific Function Receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the receptor binds to a promoter element in the gene for acyl-CoA oxidase and activates its transcription. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis
Target 1 Pathways Not Available
Target 1 Reactions Not Available
Target 1 Pfam Domain Function
Target 1 Signals
  • None
Target 1 Transmembrane Regions
  • None
Target 1 Essentiality Non-Essential
Target 1 GenBank ID Protein 1711117 Link Image
Target 1 UniProtKB/Swiss-Prot ID P37231 Link Image
Target 1 UniProtKB/Swiss-Prot Entry Name PPARG_HUMAN Link Image
Target 1 PDB ID 1I7I Link Image
Target 1 PDB File Show
Target 1 3D Structure
Target 1 Cellular Location
  • Nucleus
Target 1 Gene Sequence >1518 bp 
ATGGGTGAAACTCTGGGAGATTCTCCTATTGACCCAGAAAGCGATTCCTTCACTGATACA
CTGTCTGCAAACATATCACAAGAAATGACCATGGTTGACACAGAGATGCCATTCTGGCCC
ACCAACTTTGGGATCAGCTCCGTGGATCTCTCCGTAATGGAAGACCACTCCCACTCCTTT
GATATCAAGCCCTTCACTACTGTTGACTTCTCCAGCATTTCTACTCCACATTACGAAGAC
ATTCCATTCACAAGAACAGATCCAGTGGTTGCAGATTACAAGTATGACCTGAAACTTCAA
GAGTACCAAAGTGCAATCAAAGTGGAGCCTGCATCTCCACCTTATTATTCTGAGAAGACT
CAGCTCTACAATAAGCCTCATGAAGAGCCTTCCAACTCCCTCATGGCAATTGAATGTCGT
GTCTGTGGAGATAAAGCTTCTGGATTTCACTATGGAGTTCATGCTTGTGAAGGATGCAAG
GGTTTCTTCCGGAGAACAATCAGATTGAAGCTTATCTATGACAGATGTGATCTTAACTGT
CGGATCCACAAAAAAAGTAGAAATAAATGTCAGTACTGTCGGTTTCAGAAATGCCTTGCA
GTGGGGATGTCTCATAATGCCATCAGGTTTGGGCGGATGCCACAGGCCGAGAAGGAGAAG
CTGTTGGCGGAGATCTCCAGTGATATCGACCAGCTGAATCCAGAGTCCGCTGACCTCCGG
GCCCTGGCAAAACATTTGTATGACTCATACATAAAGTCCTTCCCGCTGACCAAAGCAAAG
GCGAGGGCGATCTTGACAGGAAAGACAACAGACAAATCACCATTCGTTATCTATGACATG
AATTCCTTAATGATGGGAGAAGATAAAATCAAGTTCAAACACATCACCCCCCTGCAGGAG
CAGAGCAAAGAGGTGGCCATCCGCATCTTTCAGGGCTGCCAGTTTCGCTCCGTGGAGGCT
GTGCAGGAGATCACAGAGTATGCCAAAAGCATTCCTGGTTTTGTAAATCTTGACTTGAAC
GACCAAGTAACTCTCCTCAAATATGGAGTCCACGAGATCATTTACACAATGCTGGCCTCC
TTGATGAATAAAGATGGGGTTCTCATATCCGAGGGCCAAGGCTTCATGACAAGGGAGTTT
CTAAAGAGCCTGCGAAAGCCTTTTGGTGACTTTATGGAGCCCAAGTTTGAGTTTGCTGTG
AAGTTCAATGCACTGGAATTAGATGACAGCGACTTGGCAATATTTATTGCTGTCATTATT
CTCAGTGGAGACCGCCCAGGTTTGCTGAATGTGAAGCCCATTGAAGACATTCAAGACAAC
CTGCTACAAGCCCTGGAGCTCCAGCTGAAGCTGAACCACCCTGAGTCCTCACAGCTGTTT
GCCAAGCTGCTCCAGAAAATGACAGACCTCAGACAGATTGTCACGGAACACGTGCAGCTA
CTGCAGGTGATCAAGAAGACGGAGACAGACATGAGTCTTCACCCGCTCCTGCAGGAGATC
TACAAGGACTTGTACTAG
Target 1 GenBank Gene ID
Target 1 GeneCard ID PPARG Link Image
Target 1 GenAtlas ID PPARG Link Image
Target 1 HGNC ID HGNC:9236 Link Image
Target 1 Chromosome Location 3
Target 1 Locus 3p25
Target 1 SNPs SNPJam Report Link Image
Target 1 General References
  1. Sarraf P, Mueller E, Smith WM, Wright HM, Kum JB, Aaltonen LA, de la Chapelle A, Spiegelman BM, Eng C: Loss-of-function mutations in PPAR gamma associated with human colon cancer. Mol Cell. 1999 Jun;3(6):799-804. [PubMed Link Image]
  2. Hamann A, Munzberg H, Buttron P, Busing B, Hinney A, Mayer H, Siegfried W, Hebebrand J, Greten H: Missense variants in the human peroxisome proliferator-activated receptor-gamma2 gene in lean and obese subjects. Eur J Endocrinol. 1999 Jul;141(1):90-2. [PubMed Link Image]
  3. Barroso I, Gurnell M, Crowley VE, Agostini M, Schwabe JW, Soos MA, Maslen GL, Williams TD, Lewis H, Schafer AJ, Chatterjee VK, O'Rahilly S: Dominant negative mutations in human PPARgamma associated with severe insulin resistance, diabetes mellitus and hypertension. Nature. 1999 Dec 23-30;402(6764):880-3. [PubMed Link Image]
  4. Caira F, Antonson P, Pelto-Huikko M, Treuter E, Gustafsson JA: Cloning and characterization of RAP250, a novel nuclear receptor coactivator. J Biol Chem. 2000 Feb 25;275(8):5308-17. [PubMed Link Image]
  5. Gampe RT Jr, Montana VG, Lambert MH, Miller AB, Bledsoe RK, Milburn MV, Kliewer SA, Willson TM, Xu HE: Asymmetry in the PPARgamma/RXRalpha crystal structure reveals the molecular basis of heterodimerization among nuclear receptors. Mol Cell. 2000 Mar;5(3):545-55. [PubMed Link Image]
  6. Agarwal AK, Garg A: A novel heterozygous mutation in peroxisome proliferator-activated receptor-gamma gene in a patient with familial partial lipodystrophy. J Clin Endocrinol Metab. 2002 Jan;87(1):408-11. [PubMed Link Image]
  7. Shao W, Halachmi S, Brown M: ERAP140, a conserved tissue-specific nuclear receptor coactivator. Mol Cell Biol. 2002 May;22(10):3358-72. [PubMed Link Image]
  8. Greene ME, Blumberg B, McBride OW, Yi HF, Kronquist K, Kwan K, Hsieh L, Greene G, Nimer SD: Isolation of the human peroxisome proliferator activated receptor gamma cDNA: expression in hematopoietic cells and chromosomal mapping. Gene Expr. 1995;4(4-5):281-99. [PubMed Link Image]
  9. Elbrecht A, Chen Y, Cullinan CA, Hayes N, Leibowitz M, Moller DE, Berger J: Molecular cloning, expression and characterization of human peroxisome proliferator activated receptors gamma 1 and gamma 2. Biochem Biophys Res Commun. 1996 Jul 16;224(2):431-7. [PubMed Link Image]
  10. Lambe KG, Tugwood JD: A human peroxisome-proliferator-activated receptor-gamma is activated by inducers of adipogenesis, including thiazolidinedione drugs. Eur J Biochem. 1996 Jul 1;239(1):1-7. [PubMed Link Image]
  11. 9065481 Mukherjee R, Jow L, Croston GE, Paterniti JR Jr: Identification, characterization, and tissue distribution of human peroxisome proliferator-activated receptor (PPAR) isoforms PPARgamma2 versus PPARgamma1 and activation with retinoid X receptor agonists and antagonists. J Biol Chem. 1997 Mar 21;272(12):8071-6.
  12. 9144532 Yanase T, Yashiro T, Takitani K, Kato S, Taniguchi S, Takayanagi R, Nawata H: Differential expression of PPAR gamma1 and gamma2 isoforms in human adipose tissue. Biochem Biophys Res Commun. 1997 Apr 17;233(2):320-4.
  13. 9356045 Okazawa H, Mori H, Tamori Y, Araki S, Niki T, Masugi J, Kawanishi M, Kubota T, Shinoda H, Kasuga M: No coding mutations are detected in the peroxisome proliferator-activated receptor-gamma gene in Japanese patients with lipoatrophic diabetes. Diabetes. 1997 Nov;46(11):1904-6.
  14. 9425261 Yen CJ, Beamer BA, Negri C, Silver K, Brown KA, Yarnall DP, Burns DK, Roth J, Shuldiner AR: Molecular scanning of the human peroxisome proliferator activated receptor gamma (hPPAR gamma) gene in diabetic Caucasians: identification of a Pro12Ala PPAR gamma 2 missense mutation. Biochem Biophys Res Commun. 1997 Dec 18;241(2):270-4.
  15. 9753710 Ristow M, Muller-Wieland D, Pfeiffer A, Krone W, Kahn CR: Obesity associated with a mutation in a genetic regulator of adipocyte differentiation. N Engl J Med. 1998 Oct 1;339(14):953-9.
Target 1 Drug 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 Link Image]
  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 Link Image]
  3. Kameda N, Okuya S, Oka Y: [Rosiglitazone (BRL-49653)] Nippon Rinsho. 2000 Feb;58(2):401-4. [PubMed Link Image]
  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 Link Image]
  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 Link Image]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed Link Image]

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.