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Identification
NameEpoprostenol
Accession NumberDB01240  (APRD00949)
TypeSmall Molecule
GroupsApproved
Description

A prostaglandin that is a powerful vasodilator and inhibits platelet aggregation. It is biosynthesized enzymatically from prostaglandin endoperoxides in human vascular tissue. The sodium salt has been also used to treat primary pulmonary hypertension.

Structure
Thumb
Synonyms
(5Z,13e)-(15S)-6,9alpha-Epoxy-11alpha,15-dihydroxyprosta-5,13-dienoate
(5Z,9alpha,11alpha,13e,15S)-6,9-Epoxy-11,15-dihydroxyprosta-5,13-dien-1-oic acid
Epoprostenol
Flolan
PGI2
PGX
Prostacyclin
Prostaglandin I2
Prostaglandin x
Vasocyclin
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Caripulpowder for solution0.5 mgintravenousActelion Pharmaceuticals Ltd2013-04-24Not applicableCanada
Caripulpowder for solution1.5 mgintravenousActelion Pharmaceuticals Ltd2013-04-24Not applicableCanada
Epoprostenol for Injectionpowder for solution1.5 mgintravenousSandoz Canada IncorporatedNot applicableNot applicableCanada
Epoprostenol for Injectionpowder for solution0.5 mgintravenousSandoz Canada IncorporatedNot applicableNot applicableCanada
Flolaninjection, powder, lyophilized, for solution.5 mg/1intravenousGlaxo Smith Kline Llc1995-12-08Not applicableUs
Flolanpowder for solution1.5 mgintravenousGlaxosmithkline Inc1997-07-28Not applicableCanada
Flolanpowder for solution0.5 mgintravenousGlaxosmithkline Inc1997-07-28Not applicableCanada
Flolaninjection, powder, lyophilized, for solution1.5 mg/1intravenousGlaxo Smith Kline Llc1995-12-08Not applicableUs
Veletriinjection, powder, lyophilized, for solution500000 ng/10mLintravenousActelion Pharmaceuticals US, Inc.2010-04-22Not applicableUs
Veletriinjection, powder, lyophilized, for solution1500000 ng/10mLintravenousActelion Pharmaceuticals US, Inc.2010-04-22Not applicableUs
Veletriinjection, powder, lyophilized, for solution1500000 ng/10mLintravenousActelion Pharmaceuticals US, Inc.2010-04-22Not applicableUs
Approved Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Epoprostenol Sodiuminjection, powder, for solution.5 mg/1intravenousTeva Parenteral Medicines, Inc.2008-04-23Not applicableUs
Epoprostenol Sodiuminjection, powder, for solution1.5 mg/1intravenousTeva Parenteral Medicines, Inc.2008-04-23Not applicableUs
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Epoprostenol sodium
ThumbNot applicableDBSALT001218
Categories
UNIIDCR9Z582X0
CAS number35121-78-9
WeightAverage: 352.4651
Monoisotopic: 352.224974134
Chemical FormulaC20H32O5
InChI KeyInChIKey=KAQKFAOMNZTLHT-OZUDYXHBSA-N
InChI
InChI=1S/C20H32O5/c1-2-3-4-7-14(21)10-11-16-17-12-15(8-5-6-9-20(23)24)25-19(17)13-18(16)22/h8,10-11,14,16-19,21-22H,2-7,9,12-13H2,1H3,(H,23,24)/b11-10+,15-8-/t14-,16+,17+,18+,19-/m0/s1
IUPAC Name
5-[(3aR,4R,5R,6aS)-5-hydroxy-4-[(1E,3S)-3-hydroxyoct-1-en-1-yl]-hexahydro-2H-cyclopenta[b]furan-2-ylidene]pentanoic acid
SMILES
[H][C@]12C[C@@H](O)[[email protected]](\C=C\[C@@H](O)CCCCC)[C@@]1([H])CC(O2)=CCCCC(O)=O
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as prostaglandins and related compounds. These are unsaturated carboxylic acids consisting of a 20 carbon skeleton that also contains a five member ring, and are based upon the fatty acid arachidonic acid.
KingdomOrganic compounds
Super ClassLipids and lipid-like molecules
ClassFatty Acyls
Sub ClassEicosanoids
Direct ParentProstaglandins and related compounds
Alternative Parents
Substituents
  • Prostaglandin skeleton
  • Medium-chain hydroxy acid
  • Fatty alcohol
  • Medium-chain fatty acid
  • Heterocyclic fatty acid
  • Oxolane
  • Cyclic alcohol
  • Secondary alcohol
  • Oxacycle
  • Organoheterocyclic compound
  • Monocarboxylic acid or derivatives
  • Carboxylic acid
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Organooxygen compound
  • Carbonyl group
  • Alcohol
  • Aliphatic heteropolycyclic compound
Molecular FrameworkAliphatic heteropolycyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationFor the long-term intravenous treatment of primary pulmonary hypertension and pulmonary hypertension associated with the scleroderma spectrum of disease in NYHA Class III and Class IV patients who do not respond adequately to conventional therapy.
PharmacodynamicsEpoprostenol has two major pharmacological actions: (1) direct vasodilation of pulmonary and systemic arterial vascular beds, and (2) inhibition of platelet aggregation. In animals, the vasodilatory effects reduce right and left ventricular afterload and increase cardiac output and stroke volume. The effect of epoprostenol on heart rate in animals varies with dose. At low doses, there is vagally mediated brudycardia, but at higher doses, epoprostenol causes reflex tachycardia in response to direct vasodilation and hypotension. No major effects on cardiac conduction have been observed. Additional pharmacologic effects of epoprostenol in animals include bronchodilation, inhibition of gastric acid secretion, and decreased gastric emptying. No available chemical assay is sufficiently sensitive and specific to assess the in vivo human pharmacokinetics of epoprostenol.
Mechanism of actionProstaglandins are present in most body tissues and fluids and mediate many biological functions. Epoprostenol (PGI2) is a member of the family of prostaglandins that is derived from arachidonic acid. The major pharmacological actions of epoprostenol is ultimately inhibition of platelet aggregation. Prostacyclin (PGI2) is released by healthy endothelial cells and performs its function through a paracrine signaling cascade that involves G protein-coupled receptors on nearby platelets and endothelial cells. The platelet Gs protein-coupled receptor (prostacyclin receptor) is activated when it binds to PGI2. This activation, in turn, signals adenylyl cyclase to produce cAMP. cAMP goes on to inhibit any undue platelet activation (in order to promote circulation) and also counteracts any increase in cytosolic calcium levels which would result from thromboxane A2 (TXA2) binding (leading to platelet activation and subsequent coagulation). PGI2 also binds to endothelial prostacyclin receptors and in the same manner raise cAMP levels in the cytosol. This cAMP then goes on to activate protein kinase A (PKA). PKA then continues the cascade by phosphorylating and inhibiting myosin light-chain kinase which leads to smooth muscle relaxation and vasodilation. Notably, PGI2 and TXA2 work as physiological antagonists.
Related Articles
AbsorptionNot Available
Volume of distribution
  • 357 mL/kg
Protein bindingNot Available
Metabolism

Epoprostenol is metabolized to 2 primary metabolites: 6-keto-PGF1α (formed by spontaneous degradation) and 6,15-diketo-13,14-dihydro-PGF1α (enzymatically formed), both of which have pharmacological activity orders of magnitude less than epoprostenol in animal test systems. Fourteen additional minor metabolites have been isolated from urine, indicating that epoprostenol is extensively metabolized in humans.

SubstrateEnzymesProduct
Epoprostenol
Not Available
6,15-Diketo-13,14-dihydro-PGF1-alphaDetails
Epoprostenol
Not Available
6-Keto-PGF1-alphaDetails
Route of eliminationEpoprostenol is metabolized to 2 primary metabolites: 6-keto-PGF1α (formed by spontaneous degradation) and 6,15-diketo-13,14-dihydro-PGF1α (enzymatically formed), both of which have pharmacological activity orders of magnitude less than epoprostenol in animal test systems. Fourteen additional minor metabolites have been isolated from urine, indicating that epoprostenol is extensively metabolized in humans.
Half lifeThe in vitro half-life of epoprostenol in human blood at 37°C and pH 7.4 is approximately 6 minutes; the in vivo half-life of epoprostenol in humans is therefore expected to be no greater than 6 minutes.
ClearanceNot Available
ToxicitySymptoms of overdose are extensions of its dose-limiting pharmacologic effects and include flushing, headache, hypotension, nausea, vomiting, and diarrhea. Most events were self-limiting and resolved with reduction or withholding of epoprostenol. Single intravenous doses at 10 and 50 mg/kg (2703 and 27,027 times the recommended acute phase human dose based on body surface area) were lethal to mice and rats, respectively. Symptoms of acute toxicity were hypoactivity, ataxia, loss of righting reflex, deep slow breathing, and hypothermia.
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+0.9922
Blood Brain Barrier+0.8767
Caco-2 permeable+0.5636
P-glycoprotein substrateSubstrate0.6946
P-glycoprotein inhibitor INon-inhibitor0.9131
P-glycoprotein inhibitor IINon-inhibitor0.8879
Renal organic cation transporterNon-inhibitor0.8878
CYP450 2C9 substrateNon-substrate0.8171
CYP450 2D6 substrateNon-substrate0.8622
CYP450 3A4 substrateSubstrate0.5384
CYP450 1A2 substrateNon-inhibitor0.5729
CYP450 2C9 inhibitorNon-inhibitor0.9251
CYP450 2D6 inhibitorNon-inhibitor0.9401
CYP450 2C19 inhibitorNon-inhibitor0.75
CYP450 3A4 inhibitorNon-inhibitor0.6126
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8673
Ames testNon AMES toxic0.7865
CarcinogenicityNon-carcinogens0.9555
BiodegradationNot ready biodegradable0.5964
Rat acute toxicity2.6928 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8304
hERG inhibition (predictor II)Non-inhibitor0.8759
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
Packagers
Dosage forms
FormRouteStrength
Injection, powder, for solutionintravenous.5 mg/1
Injection, powder, for solutionintravenous1.5 mg/1
Injection, powder, lyophilized, for solutionintravenous.5 mg/1
Injection, powder, lyophilized, for solutionintravenous1.5 mg/1
Powder for solutionintravenous0.5 mg
Powder for solutionintravenous1.5 mg
Injection, powder, lyophilized, for solutionintravenous1500000 ng/10mL
Injection, powder, lyophilized, for solutionintravenous500000 ng/10mL
Prices
Unit descriptionCostUnit
Flolan 1.5 mg vial51.59USD vial
Epoprostenol sodium 1.5 mg vial33.53USD vial
Flolan 0.5 mg vial21.36USD vial
Epoprostenol sodium 0.5 mg vial13.88USD vial
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8318802 No2007-03-152027-03-15Us
US8598227 No2007-02-022027-02-02Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
logP3Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.136 mg/mLALOGPS
logP3.83ALOGPS
logP2.42ChemAxon
logS-3.4ALOGPS
pKa (Strongest Acidic)4.43ChemAxon
pKa (Strongest Basic)-1.6ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area86.99 Å2ChemAxon
Rotatable Bond Count10ChemAxon
Refractivity99.01 m3·mol-1ChemAxon
Polarizability41.62 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis Reference

Nagesh R. Palepu, “NOVEL EPOPROSTENOL FORMULATION AND METHOD OF MAKING THEREOF.” U.S. Patent US20090088468, issued April 02, 2009.

US20090088468
General ReferencesNot Available
External Links
ATC CodesB01AC09
AHFS Codes
  • 92:00.00
PDB EntriesNot Available
FDA labelDownload (1.28 MB)
MSDSDownload (40.6 KB)
Interactions
Drug Interactions
Drug
AbciximabThe risk or severity of adverse effects can be increased when Epoprostenol is combined with Abciximab.
AcenocoumarolThe risk or severity of adverse effects can be increased when Epoprostenol is combined with Acenocoumarol.
AlteplaseThe risk or severity of adverse effects can be increased when Alteplase is combined with Epoprostenol.
AnistreplaseThe risk or severity of adverse effects can be increased when Anistreplase is combined with Epoprostenol.
Citric AcidThe risk or severity of adverse effects can be increased when Epoprostenol is combined with Citric Acid.
DalteparinThe risk or severity of adverse effects can be increased when Epoprostenol is combined with Dalteparin.
DicoumarolThe risk or severity of adverse effects can be increased when Epoprostenol is combined with Dicoumarol.
DigoxinThe serum concentration of Digoxin can be increased when it is combined with Epoprostenol.
Edetic AcidThe risk or severity of adverse effects can be increased when Epoprostenol is combined with Edetic Acid.
EnoxaparinThe risk or severity of adverse effects can be increased when Epoprostenol is combined with Enoxaparin.
Ethyl biscoumacetateThe risk or severity of adverse effects can be increased when Epoprostenol is combined with Ethyl biscoumacetate.
Fondaparinux sodiumThe risk or severity of adverse effects can be increased when Epoprostenol is combined with Fondaparinux sodium.
HeparinThe risk or severity of adverse effects can be increased when Epoprostenol is combined with Heparin.
MoxonidineEpoprostenol may increase the hypotensive activities of Moxonidine.
PhenindioneThe risk or severity of adverse effects can be increased when Epoprostenol is combined with Phenindione.
PhenprocoumonThe risk or severity of adverse effects can be increased when Epoprostenol is combined with Phenprocoumon.
ReteplaseThe risk or severity of adverse effects can be increased when Reteplase is combined with Epoprostenol.
RidogrelThe risk or severity of adverse effects can be increased when Ridogrel is combined with Epoprostenol.
StreptokinaseThe risk or severity of adverse effects can be increased when Streptokinase is combined with Epoprostenol.
SulodexideThe risk or severity of adverse effects can be increased when Epoprostenol is combined with Sulodexide.
TenecteplaseThe risk or severity of adverse effects can be increased when Tenecteplase is combined with Epoprostenol.
TreprostinilThe risk or severity of adverse effects can be increased when Epoprostenol is combined with Treprostinil.
UrokinaseThe risk or severity of adverse effects can be increased when Urokinase is combined with Epoprostenol.
WarfarinThe risk or severity of adverse effects can be increased when Epoprostenol is combined with Warfarin.
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
agonist
General Function:
Guanyl-nucleotide exchange factor activity
Specific Function:
Receptor for ADP and ATP coupled to G-proteins that inhibit the adenylyl cyclase second messenger system. Not activated by UDP and UTP. Required for normal platelet aggregation and blood coagulation.
Gene Name:
P2RY12
Uniprot ID:
Q9H244
Molecular Weight:
39438.355 Da
References
  1. Cattaneo M, Lecchi A: Inhibition of the platelet P2Y12 receptor for adenosine diphosphate potentiates the antiplatelet effect of prostacyclin. J Thromb Haemost. 2007 Mar;5(3):577-82. Epub 2006 Dec 7. [PubMed:17155953 ]
  2. Yang J, Wu J, Jiang H, Mortensen R, Austin S, Manning DR, Woulfe D, Brass LF: Signaling through Gi family members in platelets. Redundancy and specificity in the regulation of adenylyl cyclase and other effectors. J Biol Chem. 2002 Nov 29;277(48):46035-42. Epub 2002 Sep 23. [PubMed:12297509 ]
  3. Kobsar AL, Koessler J, Rajkovic MS, Brunner KP, Steigerwald U, Walter U: Prostacyclin receptor stimulation facilitates detection of human platelet P2Y(12) receptor inhibition by the PFA-100 system. Platelets. 2010;21(2):112-6. doi: 10.3109/09537100903440937. [PubMed:20085435 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
agonist
General Function:
Guanyl-nucleotide exchange factor activity
Specific Function:
Receptor for prostacyclin (prostaglandin I2 or PGI2). The activity of this receptor is mediated by G(s) proteins which activate adenylate cyclase.
Gene Name:
PTGIR
Uniprot ID:
P43119
Molecular Weight:
40955.485 Da
References
  1. Kasza Z, Fetalvero KM, Ding M, Wagner RJ, Acs K, Guzman AK, Douville KL, Powell RJ, Hwa J, Martin KA: Novel signaling pathways promote a paracrine wave of prostacyclin-induced vascular smooth muscle differentiation. J Mol Cell Cardiol. 2009 May;46(5):682-94. doi: 10.1016/j.yjmcc.2009.01.006. Epub 2009 Jan 23. [PubMed:19302827 ]
  2. Yang J, Wu J, Jiang H, Mortensen R, Austin S, Manning DR, Woulfe D, Brass LF: Signaling through Gi family members in platelets. Redundancy and specificity in the regulation of adenylyl cyclase and other effectors. J Biol Chem. 2002 Nov 29;277(48):46035-42. Epub 2002 Sep 23. [PubMed:12297509 ]
  3. Ibrahim S, Tetruashvily M, Frey AJ, Wilson SJ, Stitham J, Hwa J, Smyth EM: Dominant negative actions of human prostacyclin receptor variant through dimerization: implications for cardiovascular disease. Arterioscler Thromb Vasc Biol. 2010 Sep;30(9):1802-9. doi: 10.1161/ATVBAHA.110.208900. Epub 2010 Jun 3. [PubMed:20522800 ]
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inducer
General Function:
Prostaglandin-i synthase activity
Specific Function:
Catalyzes the isomerization of prostaglandin H2 to prostacyclin (= prostaglandin I2).
Gene Name:
PTGIS
Uniprot ID:
Q16647
Molecular Weight:
57103.385 Da
References
  1. Nakayama T: Genetic polymorphisms of prostacyclin synthase gene and cardiovascular disease. Int Angiol. 2010 Apr;29(2 Suppl):33-42. [PubMed:20357747 ]
  2. Ruan KH, Wu J, Cervantes V: Characterization of the substrate mimic bound to engineered prostacyclin synthase in solution using high-resolution NMR spectroscopy and mutagenesis: implication of the molecular mechanism in biosynthesis of prostacyclin. Biochemistry. 2008 Jan 15;47(2):680-8. Epub 2007 Dec 15. [PubMed:18081314 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
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. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenyto...
Gene Name:
CYP2C9
Uniprot ID:
P11712
Molecular Weight:
55627.365 Da
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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
Comments
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Drug created on June 13, 2005 07:24 / Updated on August 24, 2016 01:52