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Identification
NameEltrombopag
Accession NumberDB06210
TypeSmall Molecule
GroupsApproved
Description

Eltrombopag is used to treat low blood platelet counts in adults with chronic immune (idiopathic) thrombocytopenia (ITP), when certain other medicines, or surgery to remove the spleen, have not worked well enough. ITP is a condition that may cause unusual bruising or bleeding due to an abnormally low number of platelets in the blood. Eltrombopag has also been recently approved (late 2012) for the treatment of thrombocytopenia (low blood platelet counts) in patients with chronic hepatitis C to allow them to initiate and maintain interferon-based therapy.

Structure
Thumb
Synonyms
Eltrombopag
Eltrombopagum
Promacta
External Identifiers
  • SB 497115
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Promactatablet, film coated75 mg/1oralNovartis Pharmaceuticals Corporation2016-04-012016-04-23Us
Promactatablet, film coated25 mg/1oralGlaxo Smith Kline Llc2008-11-242016-04-23Us
Promactatablet, film coated100 mg/1oralGlaxo Smith Kline Llc2014-03-102016-04-23Us
Promactatablet, film coated12.5 mg/1oralGlaxo Smith Kline Llc2012-01-022016-04-23Us
Promactatablet, film coated75 mg/1oralGlaxo Smith Kline Llc2009-01-052016-04-23Us
Promactatablet, film coated50 mg/1oralNovartis Pharmaceuticals Corporation2016-04-072016-04-23Us
Promactatablet, film coated50 mg/1oralGlaxo Smith Kline Llc2008-11-242016-04-23Us
Revoladetablet50 mgoralNovartis Pharmaceuticals Canada Inc2011-04-01Not applicableCanada
Revoladetablet25 mgoralNovartis Pharmaceuticals Canada Inc2011-04-04Not applicableCanada
Revoladetablet75 mgoralNovartis Pharmaceuticals Canada IncNot applicableNot applicableCanada
Generic Prescription ProductsNot Available
Over the Counter ProductsNot Available
International BrandsNot Available
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Eltrombopag Olamine
496775-62-3
Thumb
  • InChI Key: TYYXAUPVEKKAFG-HTQZHWFGSA-N
  • Monoisotopic Mass: 564.269632914
  • Average Mass: 564.6327
DBSALT000063
Categories
UNIIS56D65XJ9G
CAS number496775-61-2
WeightAverage: 442.4666
Monoisotopic: 442.164105212
Chemical FormulaC25H22N4O4
InChI KeyInChIKey=XDXWLKQMMKQXPV-QYQHSDTDSA-N
InChI
InChI=1S/C25H22N4O4/c1-14-10-11-19(12-15(14)2)29-24(31)22(16(3)28-29)27-26-21-9-5-8-20(23(21)30)17-6-4-7-18(13-17)25(32)33/h4-13,26,30H,1-3H3,(H,32,33)/b27-22-
IUPAC Name
3-(3-{2-[(4Z)-1-(3,4-dimethylphenyl)-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-ylidene]hydrazin-1-yl}-2-hydroxyphenyl)benzoic acid
SMILES
CC1=NN(C(=O)\C1=N/NC1=C(O)C(=CC=C1)C1=CC=CC(=C1)C(O)=O)C1=CC=C(C)C(C)=C1
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as biphenyls and derivatives. These are organic compounds containing to benzene rings linked together by a C-C bond.
KingdomOrganic compounds
Super ClassBenzenoids
ClassBenzene and substituted derivatives
Sub ClassBiphenyls and derivatives
Direct ParentBiphenyls and derivatives
Alternative Parents
Substituents
  • Biphenyl
  • Benzoic acid
  • Benzoic acid or derivatives
  • Phenylhydrazine
  • Benzoyl
  • Phenol
  • Pyrazolinone
  • Pyrazoline
  • Hydrazone
  • Carboxamide group
  • Azacycle
  • Organoheterocyclic compound
  • Monocarboxylic acid or derivatives
  • Carboxylic acid
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Carbonyl group
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationThrombopoietin receptor agonists are pharmaceutical agents that stimulate platelet production in the bone marrow. In this, they differ from the previously discussed agents that act by attempting to curtail platelet destruction.
PharmacodynamicsNot Available
Mechanism of actionEltrombopag is an orally bioavailable, small-molecule TPO-receptor agonist that interacts with the transmembrane domain of the human TPO-receptor. Eltrombopag is a stimulator of STAT and JAK phosphorylation. Unlike recombinant TPO or romiplostim, Eltrombopag does not activate the AKT pathway in any way. It should be noted that when given to patients with aplastic anemia, other lineages besides platelet count were increased, suggesting that either eltrombopag enhanced the effect of TPO in vivo; or there is a yet uncovered mechanism of action at work.
Related Articles
AbsorptionPeak absorption of Eltrombopag occurs around 2-6 hours following oral administration, and the total oral absorption of drug-related material following a 75 mg dose was estimated to be at least 52%.
Volume of distribution

Based on a radiolabel study, the concentration of eltrombopag in blood cells is approximately 50% to 79% of plasma concentrations.

Protein bindingEltrombopag is highly protein bound (>99%).
Metabolism

Eltrombopag is predominantly through pathways including cleavage, oxidation, and conjugation with glucuronic acid, glutathione, or cysteine. In vitro studies suggest that CYP1A2 and CYP2C8 are responsible for the oxidative metabolism of eltrombopag. UGT1A1 and UGT1A3 are responsible for the glucuronidation of eltrombopag.

Route of eliminationEltrombopag is eliminated primarily via the feces (59%), along with 31% being renally excreted.
Half lifeAbout 21-32 hours in healthy patients. About 26-35 hours in patients with idiopathic thrombocytopenic purpura.
ClearanceNot Available
ToxicityEltrombopag may cause hepatotoxicity, especially if administered in combination with interferon and ribavirin in patients with chronic hepatitis C (may increase the risk of hepatic decompensation).
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.6946
Blood Brain Barrier-0.6616
Caco-2 permeable-0.5811
P-glycoprotein substrateNon-substrate0.6578
P-glycoprotein inhibitor INon-inhibitor0.8297
P-glycoprotein inhibitor IINon-inhibitor0.9187
Renal organic cation transporterNon-inhibitor0.944
CYP450 2C9 substrateNon-substrate0.5991
CYP450 2D6 substrateNon-substrate0.8495
CYP450 3A4 substrateSubstrate0.5424
CYP450 1A2 substrateNon-inhibitor0.8173
CYP450 2C9 inhibitorInhibitor0.6357
CYP450 2D6 inhibitorNon-inhibitor0.8982
CYP450 2C19 inhibitorNon-inhibitor0.7625
CYP450 3A4 inhibitorNon-inhibitor0.7595
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.6304
Ames testNon AMES toxic0.5993
CarcinogenicityNon-carcinogens0.5481
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.1796 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9862
hERG inhibition (predictor II)Non-inhibitor0.6936
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Tablet, film coatedoral100 mg/1
Tablet, film coatedoral12.5 mg/1
Tablet, film coatedoral25 mg/1
Tablet, film coatedoral50 mg/1
Tablet, film coatedoral75 mg/1
Tabletoral25 mg
Tabletoral50 mg
Tabletoral75 mg
PricesNot Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US6280959 Yes1999-04-302019-04-30Us
US7160870 Yes2003-05-202023-05-20Us
US7332481 Yes2001-11-242021-11-24Us
US7452874 Yes2001-11-242021-11-24Us
US7473686 Yes2001-11-242021-11-24Us
US7547719 Yes2006-01-132026-01-13Us
US7790704 Yes2001-11-242021-11-24Us
US7795293 Yes2003-11-212023-11-21Us
US8052993 Yes2008-02-012028-02-01Us
US8052994 Yes2008-02-012028-02-01Us
US8052995 Yes2008-02-012028-02-01Us
US8062665 Yes2008-02-012028-02-01Us
US8071129 Yes2008-02-012028-02-01Us
US8828430 Yes2008-02-012028-02-01Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
water solubilityEltrombopag olamine is practically insoluble in aqueous buffer across a pH range of 1 to 7.4, and is sparingly soluble in water.FDA Label
Predicted Properties
PropertyValueSource
Water Solubility0.0103 mg/mLALOGPS
logP4.02ALOGPS
logP6.03ChemAxon
logS-4.6ALOGPS
pKa (Strongest Acidic)3.99ChemAxon
pKa (Strongest Basic)0.17ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area114.59 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity126.48 m3·mol-1ChemAxon
Polarizability47.64 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Download (91.2 KB)
SpectraNot Available
References
Synthesis Reference

http://doc.sciencenet.cn/upload/file/2011531154034454.pdf

General References
  1. Zekry A, Freiman J: Eltrombopag: Is this "24 karat gold platelet" treatment for thrombocytopenia in cirrhosis associated with hepatitis C? Hepatology. 2008 Apr;47(4):1418-21. doi: 10.1002/hep.22300. [PubMed:18366111 ]
  2. Mondelli MU: Eltrombopag: an effective remedy for thrombocytopaenia? J Hepatol. 2008 Jun;48(6):1030-2. doi: 10.1016/j.jhep.2008.03.008. Epub 2008 Mar 31. [PubMed:18433923 ]
  3. Tarantino MD, Fogarty P, Mayer B, Vasey SY, Brainsky A: Efficacy of eltrombopag in management of bleeding symptoms associated with chronic immune thrombocytopenia. Blood Coagul Fibrinolysis. 2013 Apr;24(3):284-96. doi: 10.1097/MBC.0b013e32835fac99. [PubMed:23492914 ]
  4. Kiang TK, Ensom MH, Chang TK: UDP-glucuronosyltransferases and clinical drug-drug interactions. Pharmacol Ther. 2005 Apr;106(1):97-132. Epub 2005 Jan 12. [PubMed:15781124 ]
  5. Deng Y, Madatian A, Wire MB, Bowen C, Park JW, Williams D, Peng B, Schubert E, Gorycki F, Levy M, Gorycki PD: Metabolism and disposition of eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist, in healthy human subjects. Drug Metab Dispos. 2011 Sep;39(9):1734-46. doi: 10.1124/dmd.111.040170. Epub 2011 Jun 6. [PubMed:21646437 ]
  6. Kuter DJ: The biology of thrombopoietin and thrombopoietin receptor agonists. Int J Hematol. 2013 Jul;98(1):10-23. doi: 10.1007/s12185-013-1382-0. Epub 2013 Jul 3. [PubMed:23821332 ]
External Links
ATC CodesB02BX05
AHFS Codes
  • 20:16
PDB EntriesNot Available
FDA labelDownload (197 KB)
MSDSDownload (33.7 KB)
Interactions
Drug Interactions
Drug
Aluminum hydroxideThe serum concentration of Eltrombopag can be decreased when it is combined with Aluminum hydroxide.
AtorvastatinThe serum concentration of Atorvastatin can be increased when it is combined with Eltrombopag.
BosentanThe serum concentration of Bosentan can be increased when it is combined with Eltrombopag.
Calcium AcetateThe serum concentration of Eltrombopag can be decreased when it is combined with Calcium Acetate.
Calcium carbonateThe serum concentration of Eltrombopag can be decreased when it is combined with Calcium carbonate.
Calcium ChlorideThe serum concentration of Eltrombopag can be decreased when it is combined with Calcium Chloride.
Calcium citrateThe serum concentration of Eltrombopag can be decreased when it is combined with Calcium citrate.
Calcium gluconateThe serum concentration of Eltrombopag can be decreased when it is combined with Calcium gluconate.
DeferiproneThe serum concentration of Deferiprone can be increased when it is combined with Eltrombopag.
EluxadolineThe serum concentration of Eluxadoline can be increased when it is combined with Eltrombopag.
EzetimibeThe serum concentration of Ezetimibe can be increased when it is combined with Eltrombopag.
Ferric CitrateThe serum concentration of Eltrombopag can be decreased when it is combined with Ferric Citrate.
FexofenadineThe serum concentration of Fexofenadine can be increased when it is combined with Eltrombopag.
FluvastatinThe serum concentration of Fluvastatin can be increased when it is combined with Eltrombopag.
GefitinibThe serum concentration of Gefitinib can be increased when it is combined with Eltrombopag.
IrinotecanThe serum concentration of the active metabolites of Irinotecan can be increased when Irinotecan is used in combination with Eltrombopag.
Iron DextranThe serum concentration of Eltrombopag can be decreased when it is combined with Iron Dextran.
Magnesium chlorideThe serum concentration of Eltrombopag can be decreased when it is combined with Magnesium chloride.
Magnesium citrateThe serum concentration of Eltrombopag can be decreased when it is combined with Magnesium citrate.
Magnesium hydroxideThe serum concentration of Eltrombopag can be decreased when it is combined with Magnesium hydroxide.
Magnesium oxideThe serum concentration of Eltrombopag can be decreased when it is combined with Magnesium oxide.
Magnesium salicylateThe serum concentration of Eltrombopag can be decreased when it is combined with Magnesium salicylate.
Magnesium SulfateThe serum concentration of Eltrombopag can be decreased when it is combined with Magnesium Sulfate.
MethotrexateThe serum concentration of Methotrexate can be increased when it is combined with Eltrombopag.
MitoxantroneThe serum concentration of Mitoxantrone can be increased when it is combined with Eltrombopag.
NateglinideThe serum concentration of Nateglinide can be increased when it is combined with Eltrombopag.
OlmesartanThe serum concentration of Olmesartan can be increased when it is combined with Eltrombopag.
PazopanibThe serum concentration of Pazopanib can be increased when it is combined with Eltrombopag.
PitavastatinThe serum concentration of Pitavastatin can be increased when it is combined with Eltrombopag.
PravastatinThe serum concentration of Pravastatin can be increased when it is combined with Eltrombopag.
RepaglinideThe serum concentration of Repaglinide can be increased when it is combined with Eltrombopag.
RifampicinThe serum concentration of Rifampicin can be increased when it is combined with Eltrombopag.
RiociguatThe serum concentration of Riociguat can be increased when it is combined with Eltrombopag.
RosuvastatinThe serum concentration of Rosuvastatin can be increased when it is combined with Eltrombopag.
SeleniumThe serum concentration of Eltrombopag can be decreased when it is combined with Selenium.
SimeprevirThe serum concentration of Simeprevir can be increased when it is combined with Eltrombopag.
SimvastatinThe serum concentration of Simvastatin can be increased when it is combined with Eltrombopag.
SucralfateThe serum concentration of Eltrombopag can be decreased when it is combined with Sucralfate.
Taurocholic AcidThe serum concentration of Taurocholic Acid can be increased when it is combined with Eltrombopag.
TopotecanThe serum concentration of Topotecan can be increased when it is combined with Eltrombopag.
TorasemideThe serum concentration of Torasemide can be increased when it is combined with Eltrombopag.
ValsartanThe serum concentration of Valsartan can be increased when it is combined with Eltrombopag.
ZincThe serum concentration of Eltrombopag can be decreased when it is combined with Zinc.
Zinc gluconateThe serum concentration of Eltrombopag can be decreased when it is combined with Zinc gluconate.
Zinc sulfateThe serum concentration of Eltrombopag can be decreased when it is combined with Zinc sulfate.
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
agonist
General Function:
Transmembrane signaling receptor activity
Specific Function:
Receptor for thrombopoietin. May represent a regulatory molecule specific for TPO-R-dependent immune responses.
Gene Name:
MPL
Uniprot ID:
P40238
Molecular Weight:
71244.08 Da
References
  1. Kuter DJ: Thrombopoietin and thrombopoietin mimetics in the treatment of thrombocytopenia. Annu Rev Med. 2009;60:193-206. [PubMed:19642221 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrateinhibitor
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 unrelated compounds, including steroids, fatty acids, and xenobiotics. In the epoxidation of arachidonic acid it generates only 14,15- and 11,12-cis-epoxyeicosatrienoic acids. It is the principal enzyme...
Gene Name:
CYP2C8
Uniprot ID:
P10632
Molecular Weight:
55824.275 Da
References
  1. GlaxoSmithKline. Promacta (eltrombopag) tablets prescribing information. Research Triangle Park, NC; 2009 Oct.
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrateinhibitor
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 unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N...
Gene Name:
CYP1A2
Uniprot ID:
P05177
Molecular Weight:
58293.76 Da
References
  1. GlaxoSmithKline. Promacta (eltrombopag) tablets prescribing information. Research Triangle Park, NC; 2009 Oct.
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Steroid binding
Specific Function:
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the IX-alpha-C8 and IX-alpha-C12 monoconjugates and diconjugate. Is also able to catalyze the glucuronidation of 17beta-estradiol, 17alpha-ethinylestradiol, 1-hydroxypyrene, 4-methylumbelliferone, 1-naph...
Gene Name:
UGT1A1
Uniprot ID:
P22309
Molecular Weight:
59590.91 Da
References
  1. GlaxoSmithKline. Promacta (eltrombopag) tablets prescribing information. Research Triangle Park, NC; 2009 Oct.
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Retinoic acid binding
Specific Function:
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. Isoform 2 lacks transferase activity but acts as a negative regulator of isoform 1.
Gene Name:
UGT1A3
Uniprot ID:
P35503
Molecular Weight:
60337.835 Da
References
  1. GlaxoSmithKline. Promacta (eltrombopag) tablets prescribing information. Research Triangle Park, NC; 2009 Oct.

Transporters

Kind
Protein
Organism
Human
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, prostaglandin E2, thromboxane B2, leukotriene C3, leukotriene E4, thyroxine and triiodothyronine. Involved in the clearance of bile acids and organic anions from the liver.
Gene Name:
SLCO1B1
Uniprot ID:
Q9Y6L6
Molecular Weight:
76447.99 Da
References
  1. Kuter DJ: The biology of thrombopoietin and thrombopoietin receptor agonists. Int J Hematol. 2013 Jul;98(1):10-23. doi: 10.1007/s12185-013-1382-0. Epub 2013 Jul 3. [PubMed:23821332 ]
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Drug created on March 19, 2008 10:17 / Updated on April 29, 2016 03:10