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Identification
NameIloprost
Accession NumberDB01088  (APRD01027)
TypeSmall Molecule
GroupsApproved, Investigational
Description

Iloprost is a synthetic analogue of prostacyclin PGI2. Iloprost dilates systemic and pulmonary arterial vascular beds. It is used to treat pulmonary arterial hypertension (PAH).

Structure
Thumb
SynonymsNot Available
SaltsNot Available
Brand names
NameCompany
VentavisNot Available
Brand mixturesNot Available
CategoriesNot Available
CAS number78919-13-8
WeightAverage: 478.6197
Monoisotopic: 478.271924326
Chemical FormulaC30H38O5
InChI KeyCZUMMMDKQYRZDP-JCAXBLPDSA-N
InChI
InChI=1S/C30H38O5/c1-3-4-10-21(2)27(31)16-15-25-26-18-22(17-24(26)19-28(25)32)11-8-9-14-30(34)35-20-29(33)23-12-6-5-7-13-23/h5-7,11-13,15-16,21,24-28,31-32H,8-10,14,17-20H2,1-2H3/b16-15+,22-11-
IUPAC Name
2-oxo-2-phenylethyl 5-[(2Z)-5-hydroxy-4-[(1E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl]-octahydropentalen-2-ylidene]pentanoate
SMILES
CC#CCC(C)C(O)\C=C\C1C(O)CC2C\C(CC12)=C\CCCC(=O)OCC(=O)C1=CC=CC=C1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassLipids
ClassEicosanoids
SubclassProstaglandins and related compounds
Direct parentProstaglandins and related compounds
Alternative parentsBicyclic Monoterpenes; Aromatic Monoterpenes; Fatty Alcohols; Acetophenones; Benzoyl Derivatives; Fatty Acid Esters; Secondary Alcohols; Ketones; Cyclic Alcohols and Derivatives; Carboxylic Acid Esters; Polyols; Ethers; Polyamines; Enolates; Aldehydes
Substituentsmonoterpene; aromatic monoterpene; bicyclic monoterpene; acetophenone; fatty alcohol; benzoyl; fatty acid ester; benzene; cyclic alcohol; ketone; carboxylic acid ester; secondary alcohol; polyol; polyamine; ether; carboxylic acid derivative; enolate; carbonyl group; aldehyde; alcohol
Classification descriptionThis compound belongs to the prostaglandins and related compounds. These are unsaturated carboxylic acids consisting of of a 20 carbon skeleton that also contains a five member ring, and are based upon the fatty acid arachidonic acid.
Pharmacology
IndicationUsed for the treatment of pulmonary arterial hypertension.
PharmacodynamicsIloprost is a synthetic analogue of prostacyclin PGI2. Iloprost dilates systemic and pulmonary arterial vascular beds. It also affects platelet aggregation but the relevance of this effect to the treatment of pulmonary hypertension is unknown. The two diastereoisomers of iloprost differ in their potency in dilating blood vessels, with the 4S isomer substantially more potent than the 4R isomer.
Mechanism of actionIloprost is a second generation structural analog of prostacyclin (PGI) with about ten-fold greater potency than the first generation stable analogs, such as carbaprostacyclin. Iloprost binds with equal affinity to human prostacyclin (Prostanoid IP) and prostaglandin EP1 receptors. Iloprost constricts the ilium and fundus circular smooth muscle as strongly as prostaglandin E2 (PGE2) itself. Iloprost inhibits the ADP, thrombin, and collagen-induced aggregation of human platelets. In whole animals, iloprost acts as a vasodilator, hypotensive, antidiuretic, and prolongs bleeding time. All of these properties help to antagonize the pathological changes that take place in the small pulmonary arteries of patients with pulmonary hypertension.
AbsorptionRapidly absorbed with bioavailability of 63%
Volume of distribution
  • 0.7 to 0.8 L/kg
Protein binding60%
Metabolism

Primarily hepatic. Iloprost is metabolized principally via beta-oxidation of the carboxyl side chain.

Route of eliminationNot Available
Half life20-30 minutes
Clearance
  • 20 mL/min/kg [Normal subjects]
ToxicityOverdoses can lead to hypotension, headache, flushing, nausea, vomiting, and diarrhea.
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 + 0.9543
Blood Brain Barrier + 0.5506
Caco-2 permeable + 0.5
P-glycoprotein substrate Substrate 0.7459
P-glycoprotein inhibitor I Non-inhibitor 0.6507
P-glycoprotein inhibitor II Non-inhibitor 0.8227
Renal organic cation transporter Non-inhibitor 0.8698
CYP450 2C9 substrate Non-substrate 0.8526
CYP450 2D6 substrate Non-substrate 0.8946
CYP450 3A4 substrate Substrate 0.6553
CYP450 1A2 substrate Non-inhibitor 0.5515
CYP450 2C9 substrate Non-inhibitor 0.7963
CYP450 2D6 substrate Non-inhibitor 0.8072
CYP450 2C19 substrate Non-inhibitor 0.719
CYP450 3A4 substrate Inhibitor 0.5377
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.7556
Ames test Non AMES toxic 0.7104
Carcinogenicity Non-carcinogens 0.9587
Biodegradation Not ready biodegradable 0.6052
Rat acute toxicity 2.7260 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9288
hERG inhibition (predictor II) Non-inhibitor 0.6964
Pharmacoeconomics
Manufacturers
  • Actelion pharmaceuticals ltd
Packagers
Dosage forms
FormRouteStrength
SolutionRespiratory (inhalation)
Prices
Unit descriptionCostUnit
Ventavis 10 mcg/1 ml solution74.4USDml
Ventavis 20 mcg/1 ml solution74.4USDml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
water solubilityVery slightly solubleNot Available
logP4.8Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.002ALOGPS
logP5.04ALOGPS
logP4.94ChemAxon
logS-5.4ALOGPS
pKa (Strongest Acidic)13.72ChemAxon
pKa (Strongest Basic)-0.87ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area83.83 Å2ChemAxon
Rotatable Bond Count13ChemAxon
Refractivity139.85 m3·mol-1ChemAxon
Polarizability55.4 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Spectra
SpectraNot Available
References
Synthesis ReferenceNot Available
General ReferenceNot Available
External Links
ResourceLink
PubChem Compound6443959
PubChem Substance46507818
ChemSpider4947911
Therapeutic Targets DatabaseDAP000273
PharmGKBPA164746843
RxListhttp://www.rxlist.com/cgi/generic4/ventavis.htm
Drugs.comhttp://www.drugs.com/cdi/iloprost.html
WikipediaIloprost
ATC CodesB01AC11
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelshow(244 KB)
MSDSshow(67.1 KB)
Interactions
Drug Interactions
Drug
TrandolaprilThe prostacyclin analogue, Iloprost, may increase the hypotensive effect of Trandolapril.
Food InteractionsNot Available

Targets

1. Prostacyclin receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: agonist

Components

Name UniProt ID Details
Prostacyclin receptor P43119 Details

References:

  1. Takamatsu H, Tsukada H, Watanabe Y, Cui Y, Kataoka Y, Hosoya T, Suzuki M, Watanabe Y: Specific ligand for a central type prostacyclin receptor attenuates neuronal damage in a rat model of focal cerebral ischemia. Brain Res. 2002 Jan 25;925(2):176-82. Pubmed
  2. Crutchley DJ, Solomon DE, Conanan LB: Prostacyclin analogues inhibit tissue factor expression in the human monocytic cell line THP-1 via a cyclic AMP-dependent mechanism. Arterioscler Thromb. 1992 Jun;12(6):664-70. Pubmed
  3. Schermuly RT, Pullamsetti SS, Breitenbach SC, Weissmann N, Ghofrani HA, Grimminger F, Nilius SM, Schror K, Kirchrath JM, Seeger W, Rose F: Iloprost-induced desensitization of the prostacyclin receptor in isolated rabbit lungs. Respir Res. 2007 Jan 26;8:4. Pubmed
  4. Idzko M, Hammad H, van Nimwegen M, Kool M, Vos N, Hoogsteden HC, Lambrecht BN: Inhaled iloprost suppresses the cardinal features of asthma via inhibition of airway dendritic cell function. J Clin Invest. 2007 Feb;117(2):464-72. Pubmed
  5. Tsai AL, Vijjeswarapu H, Wu KK: Interaction between platelet receptor and iloprost isomers. Biochim Biophys Acta. 1988 Jul 21;942(2):220-6. Pubmed
  6. Olschewski H, Rose F, Schermuly R, Ghofrani HA, Enke B, Olschewski A, Seeger W: Prostacyclin and its analogues in the treatment of pulmonary hypertension. Pharmacol Ther. 2004 May;102(2):139-53. Pubmed
  7. Anderson JR, Nawarskas JJ: Pharmacotherapeutic management of pulmonary arterial hypertension. Cardiol Rev. 2010 May-Jun;18(3):148-62. Pubmed
  8. Mubarak KK: A review of prostaglandin analogs in the management of patients with pulmonary arterial hypertension. Respir Med. 2010 Jan;104(1):9-21. Epub 2009 Aug 15. Pubmed
  9. Krug S, Sablotzki A, Hammerschmidt S, Wirtz H, Seyfarth HJ: Inhaled iloprost for the control of pulmonary hypertension. Vasc Health Risk Manag. 2009;5(1):465-74. Pubmed

2. Prostaglandin E2 receptor EP1 subtype

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: agonist

Components

Name UniProt ID Details
Prostaglandin E2 receptor EP1 subtype P34995 Details

References:

  1. Sharif NA, Davis TL: Cloned human EP1 prostanoid receptor pharmacology characterized using radioligand binding techniques. J Pharm Pharmacol. 2002 Apr;54(4):539-47. Pubmed
  2. Walch L, de Montpreville V, Brink C, Norel X: Prostanoid EP- and TP-receptors involved in the contraction of human pulmonary veins. Br J Pharmacol. 2001 Dec;134(8):1671-8. Pubmed

3. cAMP-specific 3',5'-cyclic phosphodiesterase 4A

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inducer

Components

Name UniProt ID Details
cAMP-specific 3',5'-cyclic phosphodiesterase 4A P27815 Details

References:

  1. Wilkens H, Guth A, Konig J, Forestier N, Cremers B, Hennen B, Bohm M, Sybrecht GW: Effect of inhaled iloprost plus oral sildenafil in patients with primary pulmonary hypertension. Circulation. 2001 Sep 11;104(11):1218-22. Pubmed
  2. Ghofrani HA, Rose F, Schermuly RT, Olschewski H, Wiedemann R, Weissmann N, Schudt C, Tenor H, Seeger W, Grimminger F: Amplification of the pulmonary vasodilatory response to inhaled iloprost by subthreshold phosphodiesterase types 3 and 4 inhibition in severe pulmonary hypertension. Crit Care Med. 2002 Nov;30(11):2489-92. Pubmed
  3. Schermuly RT, Leuchte H, Ghofrani HA, Weissmann N, Rose F, Kohstall M, Olschewski H, Schudt C, Grimminger F, Seeger W, Walmrath D: Zardaverine and aerosolised iloprost in a model of acute respiratory failure. Eur Respir J. 2003 Aug;22(2):342-7. Pubmed
  4. Grant PG, Mannarino AF, Colman RW: cAMP-mediated phosphorylation of the low-Km cAMP phosphodiesterase markedly stimulates its catalytic activity. Proc Natl Acad Sci U S A. 1988 Dec;85(23):9071-5. Pubmed

4. cAMP-specific 3',5'-cyclic phosphodiesterase 4B

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inducer

Components

Name UniProt ID Details
cAMP-specific 3',5'-cyclic phosphodiesterase 4B Q07343 Details

References:

  1. Wilkens H, Guth A, Konig J, Forestier N, Cremers B, Hennen B, Bohm M, Sybrecht GW: Effect of inhaled iloprost plus oral sildenafil in patients with primary pulmonary hypertension. Circulation. 2001 Sep 11;104(11):1218-22. Pubmed
  2. Ghofrani HA, Rose F, Schermuly RT, Olschewski H, Wiedemann R, Weissmann N, Schudt C, Tenor H, Seeger W, Grimminger F: Amplification of the pulmonary vasodilatory response to inhaled iloprost by subthreshold phosphodiesterase types 3 and 4 inhibition in severe pulmonary hypertension. Crit Care Med. 2002 Nov;30(11):2489-92. Pubmed
  3. Schermuly RT, Leuchte H, Ghofrani HA, Weissmann N, Rose F, Kohstall M, Olschewski H, Schudt C, Grimminger F, Seeger W, Walmrath D: Zardaverine and aerosolised iloprost in a model of acute respiratory failure. Eur Respir J. 2003 Aug;22(2):342-7. Pubmed
  4. Grant PG, Mannarino AF, Colman RW: cAMP-mediated phosphorylation of the low-Km cAMP phosphodiesterase markedly stimulates its catalytic activity. Proc Natl Acad Sci U S A. 1988 Dec;85(23):9071-5. Pubmed

5. cAMP-specific 3',5'-cyclic phosphodiesterase 4C

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inducer

Components

Name UniProt ID Details
cAMP-specific 3',5'-cyclic phosphodiesterase 4C Q08493 Details

References:

  1. Wilkens H, Guth A, Konig J, Forestier N, Cremers B, Hennen B, Bohm M, Sybrecht GW: Effect of inhaled iloprost plus oral sildenafil in patients with primary pulmonary hypertension. Circulation. 2001 Sep 11;104(11):1218-22. Pubmed
  2. Ghofrani HA, Rose F, Schermuly RT, Olschewski H, Wiedemann R, Weissmann N, Schudt C, Tenor H, Seeger W, Grimminger F: Amplification of the pulmonary vasodilatory response to inhaled iloprost by subthreshold phosphodiesterase types 3 and 4 inhibition in severe pulmonary hypertension. Crit Care Med. 2002 Nov;30(11):2489-92. Pubmed
  3. Schermuly RT, Leuchte H, Ghofrani HA, Weissmann N, Rose F, Kohstall M, Olschewski H, Schudt C, Grimminger F, Seeger W, Walmrath D: Zardaverine and aerosolised iloprost in a model of acute respiratory failure. Eur Respir J. 2003 Aug;22(2):342-7. Pubmed
  4. Grant PG, Mannarino AF, Colman RW: cAMP-mediated phosphorylation of the low-Km cAMP phosphodiesterase markedly stimulates its catalytic activity. Proc Natl Acad Sci U S A. 1988 Dec;85(23):9071-5. Pubmed

6. cAMP-specific 3',5'-cyclic phosphodiesterase 4D

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inducer

Components

Name UniProt ID Details
cAMP-specific 3',5'-cyclic phosphodiesterase 4D Q08499 Details

References:

  1. Wilkens H, Guth A, Konig J, Forestier N, Cremers B, Hennen B, Bohm M, Sybrecht GW: Effect of inhaled iloprost plus oral sildenafil in patients with primary pulmonary hypertension. Circulation. 2001 Sep 11;104(11):1218-22. Pubmed
  2. Ghofrani HA, Rose F, Schermuly RT, Olschewski H, Wiedemann R, Weissmann N, Schudt C, Tenor H, Seeger W, Grimminger F: Amplification of the pulmonary vasodilatory response to inhaled iloprost by subthreshold phosphodiesterase types 3 and 4 inhibition in severe pulmonary hypertension. Crit Care Med. 2002 Nov;30(11):2489-92. Pubmed
  3. Schermuly RT, Leuchte H, Ghofrani HA, Weissmann N, Rose F, Kohstall M, Olschewski H, Schudt C, Grimminger F, Seeger W, Walmrath D: Zardaverine and aerosolised iloprost in a model of acute respiratory failure. Eur Respir J. 2003 Aug;22(2):342-7. Pubmed
  4. Grant PG, Mannarino AF, Colman RW: cAMP-mediated phosphorylation of the low-Km cAMP phosphodiesterase markedly stimulates its catalytic activity. Proc Natl Acad Sci U S A. 1988 Dec;85(23):9071-5. Pubmed

7. Tissue-type plasminogen activator

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: other/unknown

Components

Name UniProt ID Details
Tissue-type plasminogen activator P00750 Details

References:

  1. Kerins DM, Roy L, Kunitada S, Adedoyin A, FitzGerald GA, Fitzgerald DJ: Pharmacokinetics of tissue-type plasminogen activator during acute myocardial infarction in men. Effect of a prostacyclin analogue. Circulation. 1992 Feb;85(2):526-32. Pubmed
  2. Nicolini FA, Mehta JL, Nichols WW, Saldeen TG, Grant M: Prostacyclin analogue iloprost decreases thrombolytic potential of tissue-type plasminogen activator in canine coronary thrombosis. Circulation. 1990 Mar;81(3):1115-22. Pubmed
  3. Nichols WW, Nicolini FA, Saldeen TG, Mehta JL: Combined thrombolytic effects of tissue-plasminogen activator and a fibrinogen-degradation product peptide 6A or iloprost. J Cardiovasc Pharmacol. 1991 Aug;18(2):231-6. Pubmed
  4. Nizankowski R, Krzanowski M, Musial J, Szczeklik A: [Effect of thromboxane A2 synthetase inhibitor and prostacyclin analogue on arterial blood pressure, fibrinolysis and platelet function in patients with hypertension] Pol Tyg Lek. 1991 Jan 7-14;46(1-3):18-21. Pubmed
  5. Herczenik E, Bouma B, Korporaal SJ, Strangi R, Zeng Q, Gros P, Van Eck M, Van Berkel TJ, Gebbink MF, Akkerman JW: Activation of human platelets by misfolded proteins. Arterioscler Thromb Vasc Biol. 2007 Jul;27(7):1657-65. Epub 2007 May 17. Pubmed

Transporters

1. Solute carrier organic anion transporter family member 2B1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Solute carrier organic anion transporter family member 2B1 O94956 Details

References:

  1. Nishio T, Adachi H, Nakagomi R, Tokui T, Sato E, Tanemoto M, Fujiwara K, Okabe M, Onogawa T, Suzuki T, Nakai D, Shiiba K, Suzuki M, Ohtani H, Kondo Y, Unno M, Ito S, Iinuma K, Nunoki K, Matsuno S, Abe T: Molecular identification of a rat novel organic anion transporter moat1, which transports prostaglandin D(2), leukotriene C(4), and taurocholate. Biochem Biophys Res Commun. 2000 Sep 7;275(3):831-8. Pubmed

2. Solute carrier organic anion transporter family member 2A1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Solute carrier organic anion transporter family member 2A1 Q92959 Details

References:

  1. Lu R, Kanai N, Bao Y, Schuster VL: Cloning, in vitro expression, and tissue distribution of a human prostaglandin transporter cDNA(hPGT). J Clin Invest. 1996 Sep 1;98(5):1142-9. Pubmed
  2. Kanai N, Lu R, Satriano JA, Bao Y, Wolkoff AW, Schuster VL: Identification and characterization of a prostaglandin transporter. Science. 1995 May 12;268(5212):866-9. Pubmed

3. Solute carrier organic anion transporter family member 3A1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Solute carrier organic anion transporter family member 3A1 Q9UIG8 Details

References:

  1. Adachi H, Suzuki T, Abe M, Asano N, Mizutamari H, Tanemoto M, Nishio T, Onogawa T, Toyohara T, Kasai S, Satoh F, Suzuki M, Tokui T, Unno M, Shimosegawa T, Matsuno S, Ito S, Abe T: Molecular characterization of human and rat organic anion transporter OATP-D. Am J Physiol Renal Physiol. 2003 Dec;285(6):F1188-97. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:13