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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
SynonymLanguageCode
EltrombopagumNot AvailableNot Available
Salts
Name/CAS Structure Properties
Eltrombopag Olamine
496775-62-3
Thumb
  • InChI Key: TYYXAUPVEKKAFG-HTQZHWFGSA-N
  • Monoisotopic Mass: 564.269632914
  • Average Mass: 564.6327
DBSALT000063
Brand names
NameCompany
PromactaGlaxoSmithKline
RevoladeGlaxoSmithKline
Brand mixturesNot Available
CategoriesNot Available
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
Mass Specshow(91.2 KB)
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassBenzene and Substituted Derivatives
SubclassBiphenyls and Derivatives
Direct parentBiphenyls and Derivatives
Alternative parentsBenzoic Acids; Aminophenols; Benzoyl Derivatives; Phenylhydrazines; Toluenes; Pyrazolones; Hydrazones; Polyols; Carboxylic Acids; Carboxylic Acid Amides; Enolates; Polyamines; Enols
Substituentsbenzoic acid; benzoic acid or derivative; aminophenol; phenylhydrazine; benzoyl; phenol derivative; toluene; pyrazolinone; pyrazoline; hydrazone; polyol; carboxamide group; enol; polyamine; carboxylic acid; enolate; carboxylic acid derivative; organonitrogen compound; amine
Classification descriptionThis compound belongs to the biphenyls and derivatives. These are organic compounds containing to benzene rings linked together by a C-C bond.
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.
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
Property Value Probability
Human Intestinal Absorption + 0.6946
Blood Brain Barrier - 0.6616
Caco-2 permeable - 0.5811
P-glycoprotein substrate Non-substrate 0.6578
P-glycoprotein inhibitor I Non-inhibitor 0.8297
P-glycoprotein inhibitor II Non-inhibitor 0.9187
Renal organic cation transporter Non-inhibitor 0.944
CYP450 2C9 substrate Non-substrate 0.5991
CYP450 2D6 substrate Non-substrate 0.8495
CYP450 3A4 substrate Substrate 0.5424
CYP450 1A2 substrate Non-inhibitor 0.8173
CYP450 2C9 substrate Inhibitor 0.6357
CYP450 2D6 substrate Non-inhibitor 0.8982
CYP450 2C19 substrate Non-inhibitor 0.7625
CYP450 3A4 substrate Non-inhibitor 0.7595
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.6304
Ames test Non AMES toxic 0.5993
Carcinogenicity Non-carcinogens 0.5481
Biodegradation Not ready biodegradable 1.0
Rat acute toxicity 2.1796 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9862
hERG inhibition (predictor II) Non-inhibitor 0.6936
Pharmacoeconomics
Manufacturers
  • Glaxosmithkline
PackagersNot Available
Dosage forms
FormRouteStrength
Tablet, coatedOral100 mg (green)
Tablet, coatedOral12.5 mg (white)
Tablet, coatedOral25 mg (orange)
Tablet, coatedOral50 mg (blue)
Tablet, coatedOral75 mg (pink)
PricesNot Available
Patents
CountryPatent NumberApprovedExpires (estimated)
United States75477192004-03-042024-03-04
United States62809591998-10-302018-10-30
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 solubility1.03e-02 g/lALOGPS
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 area114.59ChemAxon
rotatable bond count5ChemAxon
refractivity126.48ChemAxon
polarizability47.64ChemAxon
number of rings4ChemAxon
bioavailability1ChemAxon
rule of fiveNoChemAxon
Ghose filterNoChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

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

General Reference
  1. http://www.gsk.com/media/press-releases/2012/FDA-approves-new-indication-for-PROMACTA-eltrombopag.html
  2. 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. Pubmed
  3. Mondelli MU: Eltrombopag: An effective remedy for thrombocytopaenia? J Hepatol. 2008 Jun;48(6):1030-2. Epub 2008 Mar 31. Pubmed
  4. 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
  5. 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
  6. 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
  7. 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
External Links
ResourceLink
KEGG DrugD03978
RxListhttp://www.rxlist.com/promacta-drug.htm
Drugs.comhttp://www.drugs.com/ppa/eltrombopag.html
WikipediaEltrombopag
ATC CodesB02BX05
AHFS Codes
  • 20:16
PDB EntriesNot Available
FDA labelshow(197 KB)
MSDSshow(33.7 KB)
Interactions
Drug Interactions
Drug
AcetaminophenEltrombopag increases acetaminophen levels via decreasing metabolism. UDP-glucuronosyltransferase inhibition with unclear significance.
Acetylsalicylic acidDecreases metabolism, will increase effect/level of eltrombopag.
Aluminum hydroxideDecreases levels of eltrombopag by GI absorption inhibition.
AmiodaroneAffects hepatic enzyme CYP2C9/10 metabolism, increases effect/level of eltrombopag.
AmobarbitalAffects hepatic CYP1A2 metabolism, will decrease effect/level of eltrombopag. Affects hepatic CYP2C9/10 metabolism, will decrease effect/level of eltrombopag.
AtazanavirDecreases metabolism, will increase effect/level of eltrombopag. UDP-glucuronosyltransferase inhibition.
AtorvastatinEltrombopag increases levels of Atorvastatin via metabolism decrease.
BromfenacEltrombopag increases levels of Bromfenac via metabolism decrease.
ButabarbitalAffects hepatic CYP1A2 metabolism, will decrease effect/level of eltrombopag. Affects hepatic CYP2C9/10 metabolism, will decrease effect/level of eltrombopag.
ButalbitalAffects hepatic CYP1A2 metabolism, will decrease effect/level of eltrombopag. Affects hepatic CYP2C9/10 metabolism, will decrease effect/level of eltrombopag.
Calcium AcetateCalcium Salts such as calcium acetate may decrease the serum concentration of Eltrombopag. Separate administration of eltrombopag and any polyvalent cation (e.g., calcium-containing products) by at least 4 hours.
Calcium carbonateDecreases levels of eltrombopag by GI absorption inhibition.
Calcium ChlorideCalcium salts such as calcium chloride may decrease the serum concentration of eltrombopag. Separate administration of eltrombopag and any polyvalent cation (e.g., calcium-containing products) by at least 4 hours.
CarbamazepineAffects hepatic CYP1A2 metabolism, will decrease effect/level of eltrombopag. Affects hepatic CYP2C9/10 metabolism, will decrease effect/level of eltrombopag.
CelecoxibEltrombopag increases levels of Celecoxib via metabolism decrease.
CimetidineAffects hepatic CYP1A2 metabolism, will decrease effect/level of eltrombopag. Affects hepatic CYP2C9/10 metabolism, will decrease effect/level of eltrombopag.
CiprofloxacinAffects hepatic CYP1A2 metabolism, will increase effect/level of eltrombopag.
Citric AcidLevels of eltrombopag are decreased due to GI inhibition. Separate administration by at least 4 hours.
DiclofenacEltrombopag increases levels of Diclofenac via metabolism decrease. UDP-glucuronosyltransferase inhibition.
DiflunisalEltrombopag increases levels of Diflunisal via metabolism decrease.
DiltiazemAffects hepatic CYP1A2 metabolism, increases Eltrombopag level or affect.
EfavirenzAffects hepatic enzyme CYP2C9/10 metabolism and may increase the level of eltrombopag.
EnoxacinAffects hepatic enzyme CYP1A2 metabolism and may increase the level of eltrombopag.
ErythromycinAffects hepatic CYP1A2 metabolism, increases Eltrombopag level or affect.
Ethinyl EstradiolAffects hepatic CYP1A2 metabolism, increases Eltrombopag level or affect.
EtodolacIncreases levels of Etodolac via metabolism decrease. UDP-glucuronosyltransferase inhibition.
FenoprofenIncreases levels of Fenoprofen via metabolism decrease. UDP-glucuronosyltransferase inhibition.
FentanylIncreases levels of Fentanyl via metabolism decrease. UDP-glucuronosyltransferase inhibition.
FlurbiprofenIncreases levels of Flurbiprofen via metabolism decrease. UDP-glucuronosyltransferase inhibition.
FluvastatinIncreases levels of Fluvastatin via metabolism decrease. OATP transporter protein inhibition.
FluvoxamineAffects hepatic enzyme CYP1A2 metabolism and may increase the level of eltrombopag.
FluvoxamineAffects hepatic CYP2C9/10 metabolism, will increase effect/level of eltrombopag.
GrepafloxacinAffects hepatic enzyme CYP1A2 metabolism and may increase the level of eltrombopag.
HydrocodoneIncreases levels of Hydrocodone via metabolism decrease. UDP-glucuronosyltransferase inhibition with unclear significance.
HydromorphoneIncreases levels of Hydromorphone via metabolism decrease. UDP-glucuronosyltransferase inhibition with unclear significance.
IbuprofenIncreases levels of Ibuprofen via metabolism decrease. UDP-glucuronosyltransferase inhibition with unclear significance.
IndomethacinIncreases levels of Indomethacin via metabolism decrease. UDP-glucuronosyltransferase inhibition with unclear significance.
Iron DextranLevels of eltrombopag are decreased due to GI inhibition. Separate administration by at least 4 hours.
Iron sucroseLevels of eltrombopag are decreased due to GI inhibition. Separate administration by at least 4 hours.
IsoniazidAffects hepatic CYP1A2 metabolism, increases Eltrombopag level or affect.
KetoprofenIncreases levels of Ketoprofen via metabolism decrease. UDP-glucuronosyltransferase inhibition with unclear significance.
KetorolacIncreases levels of Ketorolac via metabolism decrease. UDP-glucuronosyltransferase inhibition with unclear significance.
LeflunomideAffects hepatic CYP2C9/10 metabolism, will increase effect/level of eltrombopag.
LevorphanolIncreases levels of Levorphanol via metabolism decrease. UDP-glucuronosyltransferase inhibition with unclear significance.
Magnesium SulfateLevels of eltrombopag are decreased due to GI inhibition. Separate administration by at least 4 hours.
Meclofenamic acidIncreases levels of Meclofenamic acid via metabolism decrease. UDP-glucuronosyltransferase inhibition with unclear significance.
Mefenamic acidIncreases levels of Mefenamic acid via metabolism decrease. UDP-glucuronosyltransferase inhibition with unclear significance.
MeloxicamIncreases levels of Meloxicam via metabolism decrease. UDP-glucuronosyltransferase inhibition with unclear significance.
MethadoneIncreases levels of Methadone via metabolism decrease. UDP-glucuronosyltransferase inhibition with unclear significance.
MethotrexateIncreases levels of Methotrexate via metabolism decrease. OATP transporter protein inhibition.
MexiletineAffects hepatic CYP1A2 metabolism, increases Eltrombopag level or affect.
MiconazoleAffects hepatic CYP2C9/10 metabolism, will increase effect/level of eltrombopag.
MorphineEltrombopag increases Morphine levels via decreasing metabolism. UDP-glucuronosyltransferase inhibition with unclear significance.
PethidineIncreases levels of Meperidine via metabolism decrease. UDP-glucuronosyltransferase inhibition with unclear significance.
Selenium SulfideLevels of eltrombopag are decreased due to GI inhibition. Separate administration by at least 4 hours.
Sodium bicarbonateLevels of eltrombopag are decreased due to GI inhibition. Separate administration by at least 4 hours.
TretinoinThe moderate CYP2C8 inhibitor, Eltrombopag, may decrease the metabolism and clearance of oral Tretinoin. Monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Eltrombopag is initiated, discontinued or dose changed.
Valproic AcidAffects hepatic CYP2C9/10 metabolism, will increase effect/level of eltrombopag.
ValsartanEltrombopag may increase the therapeutic and/or toxic effects of Valsartan. Increased Valsartan serum concentrations may be caused by inhibition of hepatic uptake and decreased metabolism. Consider dose modification, alternate therapy or monitor for changes in the therapeutic and toxic effects of Valsartan if Eltrombopag is initiated, discontinued or dose changed.
ZileutonAffects hepatic enzyme CYP1A2 metabolism and may increase the level of eltrombopag.
Food InteractionsNot Available

1. Thrombopoietin receptor

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: agonist

Components

Name UniProt ID Details
Thrombopoietin receptor P40238 Details

References:

  1. Kuter DJ: Thrombopoietin and thrombopoietin mimetics in the treatment of thrombocytopenia. Annu Rev Med. 2009;60:193-206. 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. GlaxoSmithKline. Promacta (eltrombopag) tablets prescribing information. Research Triangle Park, NC; 2009 Oct.

2. Cytochrome P450 1A2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Cytochrome P450 1A2 P05177 Details

References:

  1. GlaxoSmithKline. Promacta (eltrombopag) tablets prescribing information. Research Triangle Park, NC; 2009 Oct.

3. UDP-glucuronosyltransferase 1-1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
UDP-glucuronosyltransferase 1-1 P22309 Details

References:

  1. GlaxoSmithKline. Promacta (eltrombopag) tablets prescribing information. Research Triangle Park, NC; 2009 Oct.

4. UDP-glucuronosyltransferase 1-3

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
UDP-glucuronosyltransferase 1-3 P35503 Details

References:

  1. GlaxoSmithKline. Promacta (eltrombopag) tablets prescribing information. Research Triangle Park, NC; 2009 Oct.

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. GlaxoSmithKline. Promacta (eltrombopag) tablets prescribing information. Research Triangle Park, NC; 2009 Oct.
  2. 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

Comments
Drug created on March 19, 2008 10:17 / Updated on September 16, 2013 18:03