Identification

Name
Epoprostenol
Accession Number
DB01240  (APRD00949)
Type
Small Molecule
Groups
Approved
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
  • PGI2
  • PGX
  • Prostacyclin
  • Prostaglandin I2
  • Prostaglandin x
  • Vasocyclin
External IDs
ACT-385781A
Product Ingredients
IngredientUNIICASInChI Key
Epoprostenol sodium4K04IQ1OF461849-14-7LMHIPJMTZHDKEW-XQYLJSSYSA-M
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
CaripulPowder, for solution0.5 mgIntravenousActelion2013-04-24Not applicableCanada
CaripulPowder, for solution1.5 mgIntravenousActelion2013-04-24Not applicableCanada
EpoprostenolPowder, for solution1.5 mg/5mLIntravenousGeneraMedix Inc2008-06-272009-03-19Us
Epoprostenol for InjectionPowder, for solution0.5 mgIntravenousSandoz Canada IncorporatedNot applicableNot applicableCanada
Epoprostenol for InjectionPowder, for solution1.5 mgIntravenousSandoz Canada IncorporatedNot applicableNot applicableCanada
FlolanPowder, for solution0.5 mgIntravenousGlaxosmithkline Inc1997-07-28Not applicableCanada
FlolanInjection, powder, lyophilized, for solution1.5 mg/1IntravenousGlaxosmithkline Inc1995-12-08Not applicableUs
FlolanPowder, for solution1.5 mgIntravenousGlaxosmithkline Inc1997-07-28Not applicableCanada
FlolanInjection, powder, lyophilized, for solution0.5 mg/1IntravenousGlaxosmithkline Inc1995-12-08Not applicableUs
VeletriInjection, powder, lyophilized, for solution500000 ng/10mLIntravenousActelion2010-04-22Not applicableUs
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Epoprostenol SodiumInjection, powder, for solution0.5 mg/1IntravenousTeva Parenteral Medicines, Inc.2008-04-23Not applicableUs
Epoprostenol SodiumInjection, powder, for solution1.5 mg/1IntravenousTeva Parenteral Medicines, Inc.2008-04-23Not applicableUs
International/Other Brands
Flolan
Categories
UNII
DCR9Z582X0
CAS number
35121-78-9
Weight
Average: 352.4651
Monoisotopic: 352.224974134
Chemical Formula
C20H32O5
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-[(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])CC(O2)=CCCCC(O)=O

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.

Associated Conditions
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. 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.

TargetActionsOrganism
AP2Y purinoceptor 12
agonist
Human
AProstacyclin receptor
agonist
Human
AProstacyclin synthase
inducer
Human
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.

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
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.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(1,2,6,7-3H)TestosteroneThe therapeutic efficacy of Epoprostenol can be increased when used in combination with (1,2,6,7-3H)Testosterone.
(R)-warfarinThe risk or severity of bleeding can be increased when Epoprostenol is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of bleeding can be increased when Epoprostenol is combined with (S)-Warfarin.
1-TestosteroneThe therapeutic efficacy of Epoprostenol can be increased when used in combination with 1-Testosterone.
18-methyl-19-nortestosteroneThe therapeutic efficacy of Epoprostenol can be increased when used in combination with 18-methyl-19-nortestosterone.
4-hydroxycoumarinThe risk or severity of bleeding can be increased when Epoprostenol is combined with 4-hydroxycoumarin.
4-HydroxytestosteroneThe therapeutic efficacy of Epoprostenol can be increased when used in combination with 4-Hydroxytestosterone.
5beta-dihydrotestosteroneThe therapeutic efficacy of Epoprostenol can be increased when used in combination with 5beta-dihydrotestosterone.
AbacavirAbacavir may decrease the excretion rate of Epoprostenol which could result in a higher serum level.
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Epoprostenol.
Food Interactions
Not 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 References
Not Available
External Links
Human Metabolome Database
HMDB0001335
KEGG Drug
D00106
KEGG Compound
C01312
PubChem Compound
5280427
PubChem Substance
46507362
ChemSpider
4445566
ChEBI
15552
ChEMBL
CHEMBL1139
Therapeutic Targets Database
DAP001213
PharmGKB
PA449479
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Epoprostenol
ATC Codes
B01AC09 — Epoprostenol
AHFS Codes
  • 48:48.00 — Vasodilating Agents
FDA label
Download (1.28 MB)
MSDS
Download (40.6 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceAbdominal Surgeries / General Surgery1
1CompletedPreventionReperfusion Injury1
1CompletedTreatmentTraumatic Brain Injury (TBI)1
1TerminatedNot AvailableHeadaches / Migraines1
1TerminatedBasic ScienceAsthma, Allergic / Healthy Volunteers1
1TerminatedTreatmentSchizophrenic Disorders1
1, 2CompletedTreatmentKnee Osteoarthritis (Knee OA)1
2CompletedPreventionSubarachnoid Hemorrhage1
2CompletedTreatmentCardiac Arrest1
2RecruitingTreatmentReperfusion Injury1
2TerminatedTreatmentCongestive Heart Failure (CHF)1
2TerminatedTreatmentPulmonary Hypertension (PH)1
3CompletedTreatmentBipolar Disorder (BD)1
3CompletedTreatmentMajor Depressive Disorder (MDD)1
3CompletedTreatmentPulmonary Arterial Hypertension (PAH)2
3Unknown StatusTreatmentPersistent Fetal Circulation Syndrome1
4Active Not RecruitingTreatmentOxygenation During One Lung Ventilation1
4CompletedTreatmentAcute Pulmonary Embolism1
4CompletedTreatmentAcute Renal Failure (ARF)1
4CompletedTreatmentHeart Failure, Unspecified1
4CompletedTreatmentPeripheral Microvascular Symptoms / Type 2 Diabetes Mellitus1
4CompletedTreatmentPulmonary Arterial Hypertension (PAH)2
4CompletedTreatmentPulmonary Hypertension (PH)3
4CompletedTreatmentRhinitis1
4RecruitingBasic ScienceBacille Calmette-Guérin / Innate Immunity1
4TerminatedTreatmentPulmonary Hypertension (PH)1
Not AvailableCompletedNot AvailableCardiovascular Disease (CVD)1
Not AvailableCompletedNot AvailablePulmonary Arterial Hypertension (PAH)1
Not AvailableCompletedTreatmentAcute Respiratory Distress Syndrome (ARDS) / Pulmonary Hypertension (PH)1
Not AvailableUnknown StatusBasic ScienceHeadaches / Migraines / Vasodilatation1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • GlaxoSmithKline Inc.
  • Hollister-Stier Laboratories LLC
  • Myogen Inc.
  • Sicor Pharmaceuticals
  • Teva Pharmaceutical Industries Ltd.
Dosage forms
FormRouteStrength
Powder, for solutionIntravenous1.5 mg/5mL
Injection, powder, for solutionIntravenous0.5 mg/1
Injection, powder, for solutionIntravenous1.5 mg/1
Injection, powder, lyophilized, for solutionIntravenous0.5 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)
US8598227No2007-02-022027-02-02Us
US8318802No2007-03-152027-03-15Us

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
Polarizability41.62 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 MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This 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.
Kingdom
Organic compounds
Super Class
Lipids and lipid-like molecules
Class
Fatty Acyls
Sub Class
Eicosanoids
Direct Parent
Prostaglandins and related compounds
Alternative Parents
Medium-chain hydroxy acids and derivatives / Fatty alcohols / Medium-chain fatty acids / Hydroxy fatty acids / Heterocyclic fatty acids / Tetrahydrofurans / Secondary alcohols / Cyclic alcohols and derivatives / Oxacyclic compounds / Monocarboxylic acids and derivatives
show 4 more
Substituents
Prostaglandin skeleton / Fatty alcohol / Medium-chain hydroxy acid / Medium-chain fatty acid / Heterocyclic fatty acid / Hydroxy fatty acid / Cyclic alcohol / Tetrahydrofuran / Secondary alcohol / Organoheterocyclic compound
show 11 more
Molecular Framework
Aliphatic heteropolycyclic compounds
External Descriptors
Not 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
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. [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
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. [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
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. [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]

Drug created on June 13, 2005 07:24 / Updated on October 21, 2018 20:30