Rosiglitazone

Identification

Summary

Rosiglitazone is a thiazolidinedione indicated as an adjunct to diet and exercise to maintain glycemic control in type 2 diabetes.

Brand Names
Avandamet, Avandia
Generic Name
Rosiglitazone
DrugBank Accession Number
DB00412
Background

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.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 357.427
Monoisotopic: 357.114712179
Chemical Formula
C18H19N3O3S
Synonyms
  • (±)-5-[p-[2-(methyl-2-pyridylamino)ethoxy]benzyl]-2,4-thiazolidinedione
  • (RS)-5-{4-[2-(Methyl-2-pyridylamino)ethoxy]benzyl}-2,4-thiazolidinedion
  • Rosiglitazon
  • Rosiglitazona
  • Rosiglitazone
  • Rosiglitazonum
External IDs
  • BRL-49653
  • TDZ-01

Pharmacology

Indication

Rosiglitazone is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Adjunct therapy in management ofType 2 diabetes mellitus••••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

When 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 action

Rosiglitazone 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.

TargetActionsOrganism
APeroxisome proliferator-activated receptor gamma
agonist
Humans
ULong-chain-fatty-acid--CoA ligase 4
inhibitor
Humans
UPeroxisome proliferator-activated receptor alphaNot AvailableHumans
UPeroxisome proliferator-activated receptor deltaNot AvailableHumans
URetinoic acid receptor RXR-alphaNot AvailableHumans
URetinoic acid receptor RXR-betaNot AvailableHumans
URetinoic acid receptor RXR-gammaNot AvailableHumans
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. 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 binding

99.8% 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.

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Route of elimination

Following 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-life

3-4 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]
Adverse Effects
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Toxicity

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

Pathways
PathwayCategory
Rosiglitazone Metabolism PathwayDrug metabolism
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbacavirRosiglitazone may decrease the excretion rate of Abacavir which could result in a higher serum level.
AbametapirThe serum concentration of Rosiglitazone can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Rosiglitazone can be increased when combined with Abatacept.
AbirateroneThe metabolism of Rosiglitazone can be decreased when combined with Abiraterone.
AbrocitinibThe metabolism of Abrocitinib can be decreased when combined with Rosiglitazone.
Food Interactions
  • Take with or without food.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Rosiglitazone MaleateKX2339DP44155141-29-0SUFUKZSWUHZXAV-BTJKTKAUSA-N
Product Images
International/Other Brands
Blutab (Werrick) / DH-Rosidia (Hasan) / Diaben (Elea) / Diaglinex (Farmindustria) / Gaudil (Craveri) / Gliximina (Denver) / Naidi (Hisun) / Rogelin (Torrent) / Roglit (Gedeon Richter) / Romerol (Drug International) / Rosit (Delta) / Rosix (Garmisch) / Rossini (Trima) / Sensulin (Square) / Sheng Ao (Hengrui) / Sheng Min (ShengJiTang Pharmaceutical)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
AvandiaTablet, film coated8 mg/1OralGlaxoSmithKline LLC2011-05-252011-10-17US flag
AvandiaTablet, film coated4 mgOralSmith Kline Beecham Plc2016-09-082016-06-08EU flag
AvandiaTablet, film coated8 mg/1OralCardinal Health1999-05-282011-10-31US flag
AvandiaTablet, film coated2 mgOralSmith Kline Beecham Plc2016-09-082016-06-08EU flag
AvandiaTablet, film coated2 mgOralSmith Kline Beecham Plc2016-09-082016-06-08EU flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Dom-rosiglitazoneTablet4 mgOralDominion PharmacalNot applicableNot applicableCanada flag
Dom-rosiglitazoneTablet2 mgOralDominion PharmacalNot applicableNot applicableCanada flag
Dom-rosiglitazoneTablet8 mgOralDominion PharmacalNot applicableNot applicableCanada flag
Mylan-rosiglitazoneTablet4 mgOralMylan PharmaceuticalsNot applicableNot applicableCanada flag
Mylan-rosiglitazoneTablet2 mgOralMylan PharmaceuticalsNot applicableNot applicableCanada flag
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
AVAGLIMRosiglitazone (4 MG) + Glimepiride (4 MG)Tablet, film coatedOralSmithkline Beecham Plc2014-07-082022-08-18Italy flag
AVAGLIMRosiglitazone (8 MG) + Glimepiride (4 MG)Tablet, film coatedOralSmithkline Beecham Plc2014-07-082022-08-18Italy flag
AvandametRosiglitazone Maleate (4 mg/1) + Metformin hydrochloride (1000 mg/1)Tablet, film coatedOralGlaxosmithkline Inc2003-10-172011-11-18US flag
AvandametRosiglitazone Maleate (2 mg/1) + Metformin hydrochloride (500 mg/1)Tablet, film coatedOralGlaxosmithkline Inc2002-10-182011-11-18US flag
AvandametRosiglitazone Maleate (1 mg) + Metformin hydrochloride (500 mg)TabletOralGlaxosmithkline Inc2003-02-182013-04-05Canada flag

Categories

ATC Codes
A10BD04 — Glimepiride and rosiglitazoneA10BG02 — RosiglitazoneA10BD03 — Metformin and rosiglitazone
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as phenol ethers. These are aromatic compounds containing an ether group substituted with a benzene ring.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Phenol ethers
Sub Class
Not Available
Direct Parent
Phenol ethers
Alternative Parents
Phenoxy compounds / Dialkylarylamines / Aminopyridines and derivatives / Alkyl aryl ethers / Imidolactams / Thiazolines / Heteroaromatic compounds / Organic carbonic acids and derivatives / Propargyl-type 1,3-dipolar organic compounds / Azacyclic compounds
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Substituents
Alkyl aryl ether / Aminopyridine / Aromatic heteromonocyclic compound / Azacycle / Carbonic acid derivative / Carbonyl group / Dialkylarylamine / Ether / Heteroaromatic compound / Hydrocarbon derivative
show 15 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
aminopyridine, thiazolidenediones (CHEBI:50122)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
05V02F2KDG
CAS number
122320-73-4
InChI Key
YASAKCUCGLMORW-UHFFFAOYSA-N
InChI
InChI=1S/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

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 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. [Article]
  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. [Article]
Human Metabolome Database
HMDB0005031
KEGG Drug
D00596
PubChem Compound
77999
PubChem Substance
46504556
ChemSpider
70383
BindingDB
50030474
RxNav
84108
ChEBI
50122
ChEMBL
CHEMBL121
Therapeutic Targets Database
DAP000271
PharmGKB
PA451283
Guide to Pharmacology
GtP Drug Page
PDBe Ligand
BRL
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
PDRhealth
PDRhealth Drug Page
Wikipedia
Rosiglitazone
FDA label
Download (86.2 KB)
MSDS
Download (30 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedNot AvailableObesity / Type 2 Diabetes Mellitus1
4CompletedBasic ScienceInflammatory Bowel Diseases (IBD)1
4CompletedPreventionMenopause / Obesity / Type 2 Diabetes Mellitus1
4CompletedPreventionSchizophrenia1
4CompletedPreventionType 2 Diabetes Mellitus1

Pharmacoeconomics

Manufacturers
  • Sb pharmco puerto rico inc
  • Glaxosmithkline
Packagers
  • A-S Medication Solutions LLC
  • Atlantic Biologicals Corporation
  • Cardinal Health
  • Diversified Healthcare Services Inc.
  • GlaxoSmithKline Inc.
  • Kaiser Foundation Hospital
  • Lake Erie Medical and Surgical Supply
  • Murfreesboro Pharmaceutical Nursing Supply
  • PD-Rx Pharmaceuticals Inc.
  • Pharmacy Service Center
  • Physicians Total Care Inc.
  • Prepackage Specialists
  • Resource Optimization and Innovation LLC
  • Searle and Co.
  • Southwood Pharmaceuticals
  • Tya Pharmaceuticals
  • Vangard Labs Inc.
  • West-Ward Pharmaceuticals
Dosage Forms
FormRouteStrength
TabletOral
Tablet, film coatedOral
TabletOral2 mg
TabletOral4 mg
TabletOral8 mg
Tablet, film coatedOral1 MG
Tablet, film coatedOral2 mg/1
Tablet, film coatedOral2 MG
Tablet, film coatedOral4 MG
Tablet, film coatedOral4 mg/1
Tablet, film coatedOral8 MG
Tablet, film coatedOral8 mg/1
TabletOral2 mg/1
TabletOral4 mg/1
TabletOral8 mg/1
Prices
Unit descriptionCostUnit
Avandia 8 mg tablet8.69USD tablet
Avandia 4 mg tablet4.72USD tablet
Avandia 2 mg tablet3.22USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US5002953No1991-03-262011-09-17US flag
CA2143849No2000-04-252013-09-01Canada flag
CA1328452No1994-04-122011-04-12Canada flag
US5965584No1999-10-122016-06-19US flag
US6166042No2000-12-262016-06-19US flag
US6288095Yes2001-09-112017-08-11US flag
US7358366Yes2008-04-152020-10-19US flag
US8236345No2012-08-072022-10-07US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)122-123 °CNot Available
logP2.4Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.038 mg/mLALOGPS
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
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9861
Blood Brain Barrier+0.8994
Caco-2 permeable-0.5451
P-glycoprotein substrateSubstrate0.6535
P-glycoprotein inhibitor INon-inhibitor0.5274
P-glycoprotein inhibitor IINon-inhibitor0.6289
Renal organic cation transporterNon-inhibitor0.5203
CYP450 2C9 substrateNon-substrate0.7418
CYP450 2D6 substrateNon-substrate0.9116
CYP450 3A4 substrateSubstrate0.5744
CYP450 1A2 substrateInhibitor0.5391
CYP450 2C9 inhibitorInhibitor0.5783
CYP450 2D6 inhibitorNon-inhibitor0.846
CYP450 2C19 inhibitorInhibitor0.5884
CYP450 3A4 inhibitorNon-inhibitor0.8309
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.7213
Ames testNon AMES toxic0.687
CarcinogenicityNon-carcinogens0.9465
BiodegradationNot ready biodegradable0.8635
Rat acute toxicity2.4515 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8055
hERG inhibition (predictor II)Non-inhibitor0.7768
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-05fr-6931000000-a3ad698c8739c8f57e74
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSsplash10-0a4i-0109000000-d527d5c2b5f1de352264
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0a4i-0109000000-d527d5c2b5f1de352264
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0a4r-1609000000-585d240b82e4a1918a29
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0a4i-0309000000-a9fa2307075b611cffcc
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-052r-0904000000-ba5855fd2637ab2d83f0
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0kmi-0192000000-c48287e1ee3b1fc42e25
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-052r-1976000000-caa0559718bfc10cd84e
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0a4r-3975000000-4c763a7949fcd8ec2315
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0ab9-1911000000-d1bfe102942583d68d8d
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0udl-4910000000-7877e14c5661c290795e
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-183.5268963
predicted
DarkChem Lite v0.1.0
[M-H]-175.61668
predicted
DeepCCS 1.0 (2019)
[M+H]+183.8053963
predicted
DarkChem Lite v0.1.0
[M+H]+177.97469
predicted
DeepCCS 1.0 (2019)
[M+Na]+183.7008963
predicted
DarkChem Lite v0.1.0
[M+Na]+184.06781
predicted
DeepCCS 1.0 (2019)

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Zinc ion binding
Specific Function
Nuclear receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the nuclear receptor binds to DNA specific PPAR response elements (PPRE...
Gene Name
PPARG
Uniprot ID
P37231
Uniprot Name
Peroxisome proliferator-activated receptor gamma
Molecular Weight
57619.58 Da
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. [Article]
  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. [Article]
  3. Kameda N, Okuya S, Oka Y: [Rosiglitazone (BRL-49653)]. Nihon Rinsho. 2000 Feb;58(2):401-4. [Article]
  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. [Article]
  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. [Article]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Very long-chain fatty acid-coa ligase activity
Specific Function
Activation of long-chain fatty acids for both synthesis of cellular lipids, and degradation via beta-oxidation. Preferentially uses arachidonate and eicosapentaenoate as substrates.
Gene Name
ACSL4
Uniprot ID
O60488
Uniprot Name
Long-chain-fatty-acid--CoA ligase 4
Molecular Weight
79187.38 Da
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. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Zinc ion binding
Specific Function
Ligand-activated transcription factor. Key regulator of lipid metabolism. Activated by the endogenous ligand 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (16:0/18:1-GPC). Activated by oleyleth...
Gene Name
PPARA
Uniprot ID
Q07869
Uniprot Name
Peroxisome proliferator-activated receptor alpha
Molecular Weight
52224.595 Da
References
  1. Inoue I, Itoh F, Aoyagi S, Tazawa S, Kusama H, Akahane M, Mastunaga T, Hayashi K, Awata T, Komoda T, Katayama S: Fibrate and statin synergistically increase the transcriptional activities of PPARalpha/RXRalpha and decrease the transactivation of NFkappaB. Biochem Biophys Res Commun. 2002 Jan 11;290(1):131-9. [Article]
  2. Drevon CA: Fatty acids and expression of adipokines. Biochim Biophys Acta. 2005 May 30;1740(2):287-92. Epub 2004 Dec 8. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Zinc ion binding
Specific Function
Ligand-activated transcription factor. Receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Has a preference for poly-unsaturated fatty acids, such as gamma-lin...
Gene Name
PPARD
Uniprot ID
Q03181
Uniprot Name
Peroxisome proliferator-activated receptor delta
Molecular Weight
49902.99 Da
References
  1. Inoue I, Itoh F, Aoyagi S, Tazawa S, Kusama H, Akahane M, Mastunaga T, Hayashi K, Awata T, Komoda T, Katayama S: Fibrate and statin synergistically increase the transcriptional activities of PPARalpha/RXRalpha and decrease the transactivation of NFkappaB. Biochem Biophys Res Commun. 2002 Jan 11;290(1):131-9. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Zinc ion binding
Specific Function
Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expressi...
Gene Name
RXRA
Uniprot ID
P19793
Uniprot Name
Retinoic acid receptor RXR-alpha
Molecular Weight
50810.835 Da
References
  1. Sarath Josh MK, Pradeep S, Vijayalekshmi Amma KS, Balachandran S, Abdul Jaleel UC, Doble M, Spener F, Benjamin S: Phthalates efficiently bind to human peroxisome proliferator activated receptor and retinoid X receptor alpha, beta, gamma subtypes: an in silico approach. J Appl Toxicol. 2014 Jul;34(7):754-65. doi: 10.1002/jat.2902. Epub 2013 Jul 11. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Zinc ion binding
Specific Function
Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expressi...
Gene Name
RXRB
Uniprot ID
P28702
Uniprot Name
Retinoic acid receptor RXR-beta
Molecular Weight
56921.38 Da
References
  1. Sarath Josh MK, Pradeep S, Vijayalekshmi Amma KS, Balachandran S, Abdul Jaleel UC, Doble M, Spener F, Benjamin S: Phthalates efficiently bind to human peroxisome proliferator activated receptor and retinoid X receptor alpha, beta, gamma subtypes: an in silico approach. J Appl Toxicol. 2014 Jul;34(7):754-65. doi: 10.1002/jat.2902. Epub 2013 Jul 11. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Zinc ion binding
Specific Function
Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expressi...
Gene Name
RXRG
Uniprot ID
P48443
Uniprot Name
Retinoic acid receptor RXR-gamma
Molecular Weight
50870.72 Da
References
  1. Sarath Josh MK, Pradeep S, Vijayalekshmi Amma KS, Balachandran S, Abdul Jaleel UC, Doble M, Spener F, Benjamin S: Phthalates efficiently bind to human peroxisome proliferator activated receptor and retinoid X receptor alpha, beta, gamma subtypes: an in silico approach. J Appl Toxicol. 2014 Jul;34(7):754-65. doi: 10.1002/jat.2902. Epub 2013 Jul 11. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Prostaglandin-endoperoxide synthase activity
Specific Function
Converts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Involved in the constitutive production of prostanoids in particular in the stomach and platelets. In gas...
Gene Name
PTGS1
Uniprot ID
P23219
Uniprot Name
Prostaglandin G/H synthase 1
Molecular Weight
68685.82 Da
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. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Supporting data are limited to in vitro studies.
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. Sahi J, Black CB, Hamilton GA, Zheng X, Jolley S, Rose KA, Gilbert D, LeCluyse EL, Sinz MW: Comparative effects of thiazolidinediones on in vitro P450 enzyme induction and inhibition. Drug Metab Dispos. 2003 Apr;31(4):439-46. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. Sahi J, Black CB, Hamilton GA, Zheng X, Jolley S, Rose KA, Gilbert D, LeCluyse EL, Sinz MW: Comparative effects of thiazolidinediones on in vitro P450 enzyme induction and inhibition. Drug Metab Dispos. 2003 Apr;31(4):439-46. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inducer
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Jaakkola T, Backman JT, Neuvonen M, Neuvonen PJ: Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics of pioglitazone. Clin Pharmacol Ther. 2005 May;77(5):404-14. doi: 10.1016/j.clpt.2004.12.266. [Article]
  2. Sahi J, Black CB, Hamilton GA, Zheng X, Jolley S, Rose KA, Gilbert D, LeCluyse EL, Sinz MW: Comparative effects of thiazolidinediones on in vitro P450 enzyme induction and inhibition. Drug Metab Dispos. 2003 Apr;31(4):439-46. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inducer
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
References
  1. Sahi J, Black CB, Hamilton GA, Zheng X, Jolley S, Rose KA, Gilbert D, LeCluyse EL, Sinz MW: Comparative effects of thiazolidinediones on in vitro P450 enzyme induction and inhibition. Drug Metab Dispos. 2003 Apr;31(4):439-46. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic ...
Gene Name
CYP2E1
Uniprot ID
P05181
Uniprot Name
Cytochrome P450 2E1
Molecular Weight
56848.42 Da
References
  1. Bazargan M, Foster DJ, Davey AK, Muhlhausler BS: Rosiglitazone Metabolism in Human Liver Microsomes Using a Substrate Depletion Method. Drugs R D. 2017 Mar;17(1):189-198. doi: 10.1007/s40268-016-0166-4. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. Bazargan M, Foster DJ, Davey AK, Muhlhausler BS: Rosiglitazone Metabolism in Human Liver Microsomes Using a Substrate Depletion Method. Drugs R D. 2017 Mar;17(1):189-198. doi: 10.1007/s40268-016-0166-4. [Article]
  2. Kirchheiner J, Thomas S, Bauer S, Tomalik-Scharte D, Hering U, Doroshyenko O, Jetter A, Stehle S, Tsahuridu M, Meineke I, Brockmoller J, Fuhr U: Pharmacokinetics and pharmacodynamics of rosiglitazone in relation to CYP2C8 genotype. Clin Pharmacol Ther. 2006 Dec;80(6):657-67. doi: 10.1016/j.clpt.2006.09.008. [Article]
  3. Hruska MW, Amico JA, Langaee TY, Ferrell RE, Fitzgerald SM, Frye RF: The effect of trimethoprim on CYP2C8 mediated rosiglitazone metabolism in human liver microsomes and healthy subjects. Br J Clin Pharmacol. 2005 Jan;59(1):70-9. doi: 10.1111/j.1365-2125.2005.02263.x. [Article]
  4. Sahi J, Black CB, Hamilton GA, Zheng X, Jolley S, Rose KA, Gilbert D, LeCluyse EL, Sinz MW: Comparative effects of thiazolidinediones on in vitro P450 enzyme induction and inhibition. Drug Metab Dispos. 2003 Apr;31(4):439-46. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Bazargan M, Foster DJ, Davey AK, Muhlhausler BS: Rosiglitazone Metabolism in Human Liver Microsomes Using a Substrate Depletion Method. Drugs R D. 2017 Mar;17(1):189-198. doi: 10.1007/s40268-016-0166-4. [Article]
  2. Sahi J, Black CB, Hamilton GA, Zheng X, Jolley S, Rose KA, Gilbert D, LeCluyse EL, Sinz MW: Comparative effects of thiazolidinediones on in vitro P450 enzyme induction and inhibition. Drug Metab Dispos. 2003 Apr;31(4):439-46. [Article]
  3. Flockhart Table of Drug Interactions [Link]
  4. Rosiglitazone FDA label [File]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostagland...
Gene Name
SLCO1B1
Uniprot ID
Q9Y6L6
Uniprot Name
Solute carrier organic anion transporter family member 1B1
Molecular Weight
76447.99 Da
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. [Article]
  2. Karlgren M, Ahlin G, Bergstrom CA, Svensson R, Palm J, Artursson P: In vitro and in silico strategies to identify OATP1B1 inhibitors and predict clinical drug-drug interactions. Pharm Res. 2012 Feb;29(2):411-26. doi: 10.1007/s11095-011-0564-9. Epub 2011 Aug 23. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Transporter activity
Specific Function
Involved in the ATP-dependent secretion of bile salts into the canaliculus of hepatocytes.
Gene Name
ABCB11
Uniprot ID
O95342
Uniprot Name
Bile salt export pump
Molecular Weight
146405.83 Da
References
  1. Pedersen JM, Matsson P, Bergstrom CA, Hoogstraate J, Noren A, LeCluyse EL, Artursson P: Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11). Toxicol Sci. 2013 Dec;136(2):328-43. doi: 10.1093/toxsci/kft197. Epub 2013 Sep 6. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Virus receptor activity
Specific Function
The hepatic sodium/bile acid uptake system exhibits broad substrate specificity and transports various non-bile acid organic compounds as well. It is strictly dependent on the extracellular presenc...
Gene Name
SLC10A1
Uniprot ID
Q14973
Uniprot Name
Sodium/bile acid cotransporter
Molecular Weight
38118.64 Da
References
  1. Donkers JM, Zehnder B, van Westen GJP, Kwakkenbos MJ, IJzerman AP, Oude Elferink RPJ, Beuers U, Urban S, van de Graaf SFJ: Reduced hepatitis B and D viral entry using clinically applied drugs as novel inhibitors of the bile acid transporter NTCP. Sci Rep. 2017 Nov 10;7(1):15307. doi: 10.1038/s41598-017-15338-0. [Article]

Drug created at June 13, 2005 13:24 / Updated at March 18, 2024 16:48