Epoprostenol

Identification

Summary

Epoprostenol is a vasodilator and platelet aggregation inhibitor used for the management of primary pulmonary hypertension and pulmonary hypertension in patients with heart failure.

Brand Names
Flolan, Veletri
Generic Name
Epoprostenol
DrugBank Accession Number
DB01240
Background

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.

Type
Small Molecule
Groups
Approved
Structure
Weight
Average: 352.4651
Monoisotopic: 352.224974134
Chemical Formula
C20H32O5
Synonyms
  • (5Z,13E)-(15S)-6,9alpha-Epoxy-11alpha,15-dihydroxyprosta-5,13-dienoate
  • (5Z,9α,11α,13E,15S)-6,9-epoxy-11,15-dihydroxyprosta-5,13-dien-1-oic acid
  • Epoprostenol
  • PGI2
  • PGX
  • Prostacyclin
  • Prostaglandin I2
  • Prostaglandin X
  • Vasocyclin
External IDs
  • ACT-385781A
  • U-53,217
  • U-53217

Pharmacology

Indication

For 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.

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Diagnostic agentPulmonary arterial hypertension••• •••••
Treatment ofPulmonary arterial hypertension••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Epoprostenol 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 action

Prostaglandins 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. Prostacycline (PGI2) from endothelial cells activate G protein-coupled receptors on platelets and endothelial cells. This activation causes adenylate cyclase to produce cyclic AMP which inhibits further platelet activation and activates protein kinase A. Cyclic AMP also prevents coagulation by preventing an increase in intracellular calcium from thromboxane A2 binding. 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.

TargetActionsOrganism
AProstacyclin synthase
inducer
Humans
AP2Y purinoceptor 12
agonist
Humans
AProstacyclin receptor
agonist
Humans
Absorption

Not Available

Volume of distribution
  • 357 mL/kg
Protein binding

Not 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.

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Route of elimination

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.

Half-life

The 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.

Clearance

Not Available

Adverse Effects
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Toxicity

Symptoms 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.

Pathways
Not Available
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
AbacavirAbacavir may decrease the excretion rate of Epoprostenol which could result in a higher serum level.
AbaloparatideThe risk or severity of adverse effects can be increased when Epoprostenol is combined with Abaloparatide.
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Epoprostenol.
AbrocitinibThe risk or severity of bleeding and thrombocytopenia can be increased when Epoprostenol is combined with Abrocitinib.
AcebutololEpoprostenol may increase the hypotensive activities of Acebutolol.
Food Interactions
  • Avoid herbs and supplements with anticoagulant/antiplatelet activity. Examples include garlic, ginger, bilberry, danshen, piracetam, and ginkgo biloba.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Epoprostenol sodium4K04IQ1OF461849-14-7LMHIPJMTZHDKEW-XQYLJSSYSA-M
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
CaripulPowder, for solution0.5 mg / vialIntravenousJanssen Pharmaceuticals2013-04-24Not applicableCanada flag
CaripulPowder, for solution1.5 mg / vialIntravenousJanssen Pharmaceuticals2013-04-24Not applicableCanada flag
EpoprostenolInjection, powder, lyophilized, for solution0.5 mg/10mLIntravenousSun Pharmaceutical Industries, Inc.2020-11-01Not applicableUS flag
EpoprostenolPowder, for solution1.5 mg/5mLIntravenousGeneraMedix Inc2008-06-272009-03-19US flag
EpoprostenolInjection, powder, lyophilized, for solution1.5 mg/10mLIntravenousSun Pharmaceutical Industries, Inc.2020-11-01Not applicableUS flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
EpoprostenolInjection, powder, lyophilized, for solution1.5 mg/10mLIntravenousSun Pharmaceutical Industries, Inc.2021-01-16Not applicableUS flag
EpoprostenolInjection, powder, lyophilized, for solution0.5 mg/10mLIntravenousSun Pharmaceutical Industries, Inc.2021-01-16Not applicableUS flag
Epoprostenol SodiumInjection, powder, for solution1.5 mg/1IntravenousTeva Parenteral Medicines, Inc.2008-04-23Not applicableUS flag
Epoprostenol SodiumInjection, powder, for solution0.5 mg/1IntravenousTeva Parenteral Medicines, Inc.2008-04-23Not applicableUS flag

Categories

ATC Codes
B01AC09 — Epoprostenol
Drug Categories
Classification
Not classified
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
DCR9Z582X0
CAS number
35121-78-9
InChI Key
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-[(2Z,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)[C@H](\C=C\[C@@H](O)CCCCC)[C@@]1([H])C\C(O2)=C\CCCC(O)=O

References

Synthesis Reference

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

US20090088468
General References
Not Available
Human Metabolome Database
HMDB0001335
KEGG Drug
D00106
KEGG Compound
C01312
PubChem Compound
5280427
PubChem Substance
46507362
ChemSpider
4445566
RxNav
8814
ChEBI
15552
ChEMBL
CHEMBL1139
ZINC
ZINC000003813078
Therapeutic Targets Database
DAP001213
PharmGKB
PA449479
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Prostacyclin
FDA label
Download (1.28 MB)
MSDS
Download (40.6 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentAcute Pulmonary Embolism (PE)1
4CompletedTreatmentAcute Renal Failure (ARF)1
4CompletedTreatmentCardiovascular Disease (CVD)1
4CompletedTreatmentHeart Failure1
4CompletedTreatmentOxygenation During One Lung Ventilation1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • GlaxoSmithKline Inc.
  • Hollister-Stier Laboratories LLC
  • Myogen Inc.
  • Sicor Pharmaceuticals
  • Teva Pharmaceutical Industries Ltd.
Dosage Forms
FormRouteStrength
Powder, for solutionParenteral0.5 MG
Powder, for solutionParenteral1.5 MG
Injection, powder, for solutionParenteral
Powder, for solutionIntravenous1.5 mg/5mL
Injection, powder, for solutionIntravenous0.5 mg/1
Injection, powder, for solutionIntravenous1.5 mg/1
Powder, for solution
Injection, powder, lyophilized, for solutionIntravenous0.5 mg/1
Injection, powder, lyophilized, for solutionIntravenous1.5 mg/1
Powder, for solutionIntravenous0.5 mg / vial
Powder, for solutionIntravenous1.5 mg / vial
Powder, for solutionParenteral0.5 MG/50ML
Powder, for solutionParenteral1.5 MG/50ML
Injection, powder, for solutionParenteral0.5 mg
Injection, powder, for solutionParenteral1.5 mg
Injection, powder, for solutionIntravascular0.5 mg
Injection, powder, lyophilized, for solutionIntravenous0.5 mg/10mL
Injection, powder, lyophilized, for solutionIntravenous1.5 mg/10mL
Injection, powder, lyophilized, for solutionIntravenous1500000 ng/10mL
Injection, powder, for solution0.5 mg
Injection, powder, for solution1.5 mg
Injection, powder, for solutionIntravenous0.5 mg
Injection, powder, for solutionIntravenous1.5 mg
Injection, powder, lyophilized, for solutionIntravenous0.5 mg
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)Region
US8598227No2013-12-032027-02-02US flag
US8318802No2012-11-272027-03-15US flag

Properties

State
Solid
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
Polarizability41.09 Å3Chemaxon
Number of Rings2Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
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)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-0159-5693000000-d4cdd32893c86bb9479a
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-014r-0009000000-66915dd0b546346271ea
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0udi-0009000000-bbcd85ca2cff34879a33
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-014i-1689000000-4bf1a5bc4aa69a63bab7
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0uyi-0039000000-524ca843da5b1724b3ea
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0603-3910000000-6e84faac086df355c14c
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-01e9-0395000000-0c3529a5cb4801ec19c7
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]-216.6150855
predicted
DarkChem Lite v0.1.0
[M-H]-191.8066822
predicted
DarkChem Standard v0.1.0
[M-H]-200.93254
predicted
DeepCCS 1.0 (2019)
[M+H]+217.0788855
predicted
DarkChem Lite v0.1.0
[M+H]+217.7110855
predicted
DarkChem Lite v0.1.0
[M+H]+203.3281
predicted
DeepCCS 1.0 (2019)
[M+Na]+216.7125855
predicted
DarkChem Lite v0.1.0
[M+Na]+216.1760855
predicted
DarkChem Lite v0.1.0
[M+Na]+209.24062
predicted
DeepCCS 1.0 (2019)

Targets

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insights and accelerate drug research.
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Kind
Protein
Organism
Humans
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
Uniprot Name
Prostacyclin synthase
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. [Article]
  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. [Article]
Kind
Protein
Organism
Humans
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
Uniprot Name
P2Y purinoceptor 12
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. [Article]
  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. [Article]
  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. [Article]
Kind
Protein
Organism
Humans
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
Uniprot Name
Prostacyclin receptor
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. [Article]
  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. [Article]
  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. [Article]
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]

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