Identification

Name
Treprostinil
Accession Number
DB00374  (APRD01272)
Type
Small Molecule
Groups
Approved, Investigational
Description

Treprostinil is a synthetic analogue of prostacyclin, used to treat pulmonary hypertension.

Structure
Thumb
Synonyms
  • (1R,2R,3aS,9aS)-[[2,3,3a,4,9,9a-hexahydro-2-hydroxy- 1-[(3S)-3-hydroxyoctyl]-1H-benz[f]inden-5-yl] oxy]acetic acid
  • [[(1R,2R,3aS,9aS)-2-Hydroxy-1-[(3S)-3-hydroxyoctyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphtalen-5-yl]oxy]acetic acid
  • Treprostinil
  • Treprostinilo
  • Treprostinilum
  • Uniprost
External IDs
15AU81 / BW 15AU / LRX 15 / LRX-15 / U 62840 / UT 15 / UT-15
Product Ingredients
IngredientUNIICASInChI Key
Treprostinil diolamineH1FKG90039830354-48-8RHWRWEUCEXUUAV-ZSESPEEFSA-N
Treprostinil sodium7JZ75N2NT6289480-64-4IQKAWAUTOKVMLE-ZSESPEEFSA-M
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
OrenitramTablet, extended release2.5 mg/1OralUnited Therapeutics2013-12-20Not applicableUs
OrenitramTablet, extended release0.125 mg/1OralUnited Therapeutics2013-12-20Not applicableUs
OrenitramTablet, extended release1 mg/1OralUnited Therapeutics2013-12-20Not applicableUs
OrenitramTablet, extended release2.5 mg/1OralAvera McKennan Hospital2016-07-20Not applicableUs
OrenitramTablet, extended release5 mg/1OralUnited Therapeutics2013-12-20Not applicableUs
OrenitramTablet, extended release0.25 mg/1OralUnited Therapeutics2013-12-20Not applicableUs
RemodulinSolution10 mgIntravenous; SubcutaneousUnited Therapeutics2004-04-30Not applicableCanada
RemodulinSolution1 mgIntravenous; SubcutaneousUnited Therapeutics2004-04-30Not applicableCanada
RemodulinInjection, solution200 mg/20mLIntravenous; SubcutaneousUnited Therapeutics2002-05-22Not applicableUs
RemodulinInjection, solution50 mg/20mLIntravenous; SubcutaneousUnited Therapeutics2002-05-22Not applicableUs
Categories
UNII
RUM6K67ESG
CAS number
81846-19-7
Weight
Average: 390.5131
Monoisotopic: 390.240624198
Chemical Formula
C23H34O5
InChI Key
PAJMKGZZBBTTOY-ZFORQUDYSA-N
InChI
InChI=1S/C23H34O5/c1-2-3-4-7-17(24)9-10-18-19-11-15-6-5-8-22(28-14-23(26)27)20(15)12-16(19)13-21(18)25/h5-6,8,16-19,21,24-25H,2-4,7,9-14H2,1H3,(H,26,27)/t16-,17-,18+,19-,21+/m0/s1
IUPAC Name
2-{[(1R,2R,3aS,9aS)-2-hydroxy-1-[(3S)-3-hydroxyoctyl]-1H,2H,3H,3aH,4H,9H,9aH-cyclopenta[b]naphthalen-5-yl]oxy}acetic acid
SMILES
[H][C@]12C[C@@H](O)[C@H](CC[C@@H](O)CCCCC)[C@@]1([H])CC1=C(C2)C(OCC(O)=O)=CC=C1

Pharmacology

Indication

For use as a continuous subcutaneous infusion or intravenous infusion (for those not able to tolerate a subcutaneous infusion) for the treatment of pulmonary arterial hypertension in patients with NYHA Class II-IV symptoms to diminish symptoms associated with exercise.

Associated Conditions
Pharmacodynamics

Pulmonary arterial hypertension (PAH) is a disease in which blood pressure is abnormally high in the arteries between the heart and lungs. PAH is characterized by symptoms of shortness of breath during physical exertion. The condition can ultimately lead to heart failure. Treprostinil is a potent oral antiplatelet agent. The major pharmacologic actions of treprostinil are direct vasodilation of pulmonary and systemic arterial vascular beds and inhibition of platelet aggregation. In animals, the vasodilatory effects reduce right and left ventricular afterload and increase cardiac output and stroke volume. Other studies have shown that treprostinil causes a dose-related negative inotropic and lusitropic effect. No major effects on cardiac conduction have been observed.

Mechanism of action

The major pharmacological actions of treprostinil are direct vasodilation of pulmonary and systemic arterial vascular beds and inhibition of platelet aggregation. In addition to treprostinil's direct vasodilatory effects, it also inhibits inflammatory cytokine. As a synthetic analogue of prostacyclin, it binds to the prostacyclin receptor, which subsequently induces the aforementioned downstream effects.

TargetActionsOrganism
AProstacyclin receptor
agonist
Human
APeroxisome proliferator-activated receptor delta
agonist
Human
AP2Y purinoceptor 12
agonist
Human
Absorption

Relatively rapid and complete after subcutaneous infusion, with an absolute bioavailability approximately 100%. In patients with mild (n=4) or moderate (n=5) hepatic insufficiency and portopulmonary hypertension following a subcutaneous dose of 10 ng per kg of body weight per min for 150 mins the AUC 0-∞ was increased 3-fold and 5-fold respectively.

Volume of distribution
  • 14 L/70 kg
Protein binding

Human plasma protein binding is approximately 91% in in vitro concentrations ranging from 330 to 10,000 µ/L.

Metabolism

Substantially metabolized by the liver, but the precise enzymes responsible are unknown. Five metabolites have been described (HU1 through HU5) however, the biological activity and metabolic fate of these are unknown. The chemical structure of HU1 is unknown. The metabolite HU5 is the glucuronide conjugate of treprostinil. The other metabolites are formed by oxidation of the 3-hydroxyoctyl side chain (HU2) and subsequent additional oxidation (HU3) or dehydration (HU4). Study results of in vitro human hepatic cytochrome P450 demonstrates that treprostinil does not inhibit CYP-1A2, 2C9, 2C19, 2D6, 2E1, or 3A. Whether treprostinil induces these enzymes has not been studied.

Route of elimination
Not Available
Half life

Terminal elimination half-life is approximately 2 to 4 hours. Plasma half-life is 34 and 85 minutes for intravenous and subcutaneous infusion of the drug, respectively.

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 treprostinil.

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

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe risk or severity of bleeding can be increased when Treprostinil is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of bleeding can be increased when Treprostinil is combined with (S)-Warfarin.
4-hydroxycoumarinThe risk or severity of bleeding can be increased when Treprostinil is combined with 4-hydroxycoumarin.
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Treprostinil.
AbexinostatThe risk or severity of QTc prolongation can be increased when Treprostinil is combined with Abexinostat.
AcebutololTreprostinil may increase the hypotensive activities of Acebutolol.
AceclofenacThe risk or severity of bleeding can be increased when Treprostinil is combined with Aceclofenac.
AcemetacinThe risk or severity of bleeding can be increased when Treprostinil is combined with Acemetacin.
AcenocoumarolThe risk or severity of bleeding can be increased when Treprostinil is combined with Acenocoumarol.
AceprometazineThe risk or severity of QTc prolongation can be increased when Treprostinil is combined with Aceprometazine.
Food Interactions
Not Available

References

Synthesis Reference

Hitesh Batra, Raju Penmasta, Vijay Sharma, Sudersan M. Tuladhar, David A. Walsh, "TREPROSTINIL PRODUCTION." U.S. Patent US20110319641, issued December 29, 2011.

US20110319641
General References
Not Available
External Links
Human Metabolome Database
HMDB0014518
PubChem Compound
6918140
PubChem Substance
46504572
ChemSpider
5293353
ChEBI
50861
ChEMBL
CHEMBL1237119
Therapeutic Targets Database
DAP001214
PharmGKB
PA164768801
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Treprostinil
ATC Codes
B01AC21 — Treprostinil
AHFS Codes
  • 48:48.00 — Vasodilating Agents
FDA label
Download (223 KB)
MSDS
Download (17.4 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0RecruitingTreatmentRaynaud's Phenomenon1
1CompletedNot AvailableHealthy Volunteers2
1CompletedBasic ScienceHealthy Volunteers1
1CompletedTreatmentChronic Obstructive Pulmonary Disease (COPD) / Pulmonary Hypertension (PH)1
1CompletedTreatmentPulmonary Arterial Hypertension (PAH) / Pulmonary Hypertension (PH)2
1, 2CompletedTreatmentHealthy Volunteers1
1, 2RecruitingTreatmentIschemia Reperfusion Injury1
1, 2RecruitingTreatmentScleroderma, Systemic1
2CompletedTreatmentIdiopathic Pulmonary Fibrosis (IPF) / Interstitial Lung Disease (ILD) / Pulmonary Arterial Hypertension (PAH)1
2CompletedTreatmentPAH1
2Not Yet RecruitingTreatmentChronic Obstructive Pulmonary Disease (COPD) / Pulmonary Hypertension (PH)1
2Not Yet RecruitingTreatmentPulmonary Arterial Hypertension (PAH)1
2RecruitingPreventionRespiratory Distress Syndrome, Adult1
2RecruitingTreatmentCalcinosis / Sclerosis, Progressive Systemic1
2RecruitingTreatmentChronic Obstructive Pulmonary Disease (COPD)1
2RecruitingTreatmentPersistent Pulmonary Hypertension of the Newborn1
2TerminatedSupportive CareCongenital Heart Disease (CHD)1
2TerminatedTreatmentIdiopathic Pulmonary Fibrosis (IPF) / Pulmonary Hypertension (PH)1
2TerminatedTreatmentSclerosis, Progressive Systemic1
2WithdrawnTreatmentPulmonary Fibrosis / Pulmonary Hypertension (PH)1
2, 3Enrolling by InvitationTreatmentCombined Pulmonary Fibrosis and Emphysema / Interstitial Lung Disease (ILD) / Pulmonary Hypertension (PH)1
2, 3RecruitingTreatmentCombined Pulmonary Fibrosis and Emphysema / Interstitial Lung Disease (ILD) / Pulmonary Hypertension (PH)1
2, 3TerminatedTreatmentPeripheral Vascular Disease (PVD)1
2, 3WithdrawnPreventionTransplantation, Liver1
3Active Not RecruitingTreatmentNon-operable Chronic Thromboembolic Pulmonary Hypertension1
3CompletedTreatmentPulmonary Hypertension (PH)2
3Not Yet RecruitingPreventionPulmonary Hypertension (PH)1
3Not Yet RecruitingTreatmentPulmonary Hypertension Associated With Sickle Cell Disease1
3RecruitingTreatmentHeart Failure With Preserved Ejection Fraction (HFpEF) / Pulmonary Hypertension (PH)1
3RecruitingTreatmentPulmonary Hypertension Associated With HFpEF1
3TerminatedTreatmentCritical Limb Ischemia (CLI) / Foot Ulcers / Peripheral Vascular Disease (PVD) / Rest Leg Pain1
3WithdrawnTreatmentPulmonary Arterial Hypertension (PAH)1
4CompletedTreatmentPulmonary Arterial Hypertension (PAH)4
4CompletedTreatmentPulmonary Arterial Hypertension (PAH) / Pulmonary Hypertension (PH)1
4CompletedTreatmentPulmonary Hypertension (PH)1
4RecruitingTreatmentPulmonary Arterial Hypertension (PAH)1
4TerminatedTreatmentPulmonary Arterial Hypertension (PAH)2
4TerminatedTreatmentPulmonary Hypertension (PH)2
4Unknown StatusTreatmentPulmonary Hypertension (PH)1
4WithdrawnTreatmentPulmonary Arterial Hypertension (PAH)2
Not AvailableCompletedNot AvailablePortopulmonary Hypertension / Pulmonary Arterial Hypertension (PAH) / Pulmonary Hypertension (PH)1
Not AvailableCompletedNot AvailablePulmonary Arterial Hypertension (PAH)1
Not AvailableRecruitingNot AvailablePulmonary Arterial Hypertension (PAH)1
Not AvailableRecruitingTreatmentFontan Operation / Univentricular heart1
Not AvailableTerminatedSupportive CareCongenital Heart Disease (CHD)1

Pharmacoeconomics

Manufacturers
  • United therapeutics corp
Packagers
  • Baxter International Inc.
  • United Therapeutics Corp.
Dosage forms
FormRouteStrength
Tablet, extended releaseOral0.125 mg/1
Tablet, extended releaseOral0.25 mg/1
Tablet, extended releaseOral1 mg/1
Tablet, extended releaseOral2.5 mg/1
Tablet, extended releaseOral5 mg/1
Injection, solutionIntravenous; Subcutaneous100 mg/20mL
Injection, solutionIntravenous; Subcutaneous20 mg/20mL
Injection, solutionIntravenous; Subcutaneous200 mg/20mL
Injection, solutionIntravenous; Subcutaneous50 mg/20mL
SolutionIntravenous; Subcutaneous1 mg
SolutionIntravenous; Subcutaneous10 mg
SolutionIntravenous; Subcutaneous2.5 mg
SolutionIntravenous; Subcutaneous5 mg
InhalantOral1.74 mg/2.9mL
Prices
Unit descriptionCostUnit
Remodulin 10 mg/ml vial737.0USD ml
Remodulin 5 mg/ml vial368.5USD ml
Tyvaso inhalation starter kit185.8USD ml
Remodulin 2.5 mg/ml vial184.25USD ml
Tyvaso 1.74 mg/2.9 ml solution174.55USD ml
Tyvaso inhalation refill kit165.68USD ml
Remodulin 1 mg/ml vial73.7USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US5153222No1994-10-062014-10-06Us
US8653137No2008-09-052028-09-05Us
US8658694No2008-09-052028-09-05Us
US7999007No2009-03-292029-03-29Us
US9199908No2004-05-242024-05-24Us
US6765117No1997-10-242017-10-24Us
US8497393No2008-12-152028-12-15Us
US6521212No1998-11-132018-11-13Us
US6756033No1998-11-132018-11-13Us
US7544713No2004-07-142024-07-14Us
US9278901No2004-05-242024-05-24Us
US7417070No2006-07-302026-07-30Us
US8410169No2010-02-132030-02-13Us
US9050311No2004-05-242024-05-24Us
US8252839No2004-05-242024-05-24Us
US8747897No2009-10-082029-10-08Us
US8349892No2011-01-222031-01-22Us
US9593066No2008-12-152028-12-15Us
US9604901No2008-12-152028-12-15Us
US9339507No2008-03-102028-03-10Us
US9358240No2008-05-052028-05-05Us
US9422223No2004-05-242024-05-24Us
US9393203No2006-04-272026-04-27Us
US9713599No2004-12-162024-12-16Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilityInsoluble at 25°CNot Available
logP4.1Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00731 mg/mLALOGPS
logP3.53ALOGPS
logP4ChemAxon
logS-4.7ALOGPS
pKa (Strongest Acidic)3.76ChemAxon
pKa (Strongest Basic)-1.3ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area86.99 Å2ChemAxon
Rotatable Bond Count10ChemAxon
Refractivity108 m3·mol-1ChemAxon
Polarizability45.74 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.994
Blood Brain Barrier+0.5541
Caco-2 permeable+0.5838
P-glycoprotein substrateSubstrate0.7733
P-glycoprotein inhibitor INon-inhibitor0.719
P-glycoprotein inhibitor IINon-inhibitor0.7518
Renal organic cation transporterNon-inhibitor0.8064
CYP450 2C9 substrateNon-substrate0.7811
CYP450 2D6 substrateNon-substrate0.8144
CYP450 3A4 substrateSubstrate0.6538
CYP450 1A2 substrateInhibitor0.7312
CYP450 2C9 inhibitorNon-inhibitor0.8496
CYP450 2D6 inhibitorNon-inhibitor0.9127
CYP450 2C19 inhibitorNon-inhibitor0.6214
CYP450 3A4 inhibitorNon-inhibitor0.6587
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.6885
Ames testNon AMES toxic0.8716
CarcinogenicityNon-carcinogens0.9452
BiodegradationNot ready biodegradable0.7495
Rat acute toxicity2.0749 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9588
hERG inhibition (predictor II)Inhibitor0.7664
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-MSNot Available
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 phenoxyacetic acid derivatives. These are compounds containing an anisole where the methane group is linked to an acetic acid or a derivative.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Phenoxyacetic acid derivatives
Direct Parent
Phenoxyacetic acid derivatives
Alternative Parents
Tetralins / Fatty alcohols / Alkyl aryl ethers / Secondary alcohols / Cyclic alcohols and derivatives / Monocarboxylic acids and derivatives / Carboxylic acids / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds
Substituents
Phenoxyacetate / Tetralin / Fatty alcohol / Alkyl aryl ether / Fatty acyl / Cyclic alcohol / Secondary alcohol / Carboxylic acid derivative / Carboxylic acid / Ether
Molecular Framework
Aromatic homopolycyclic compounds
External Descriptors
carboxylic acid, carbotricyclic compound (CHEBI:50861)

Targets

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. Falcetti E, Hall SM, Phillips PG, Patel J, Morrell NW, Haworth SG, Clapp LH: Smooth muscle proliferation and role of the prostacyclin (IP) receptor in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med. 2010 Nov 1;182(9):1161-70. doi: 10.1164/rccm.201001-0011OC. Epub 2010 Jul 9. [PubMed:20622039]
  2. Sprague RS, Bowles EA, Hanson MS, DuFaux EA, Sridharan M, Adderley S, Ellsworth ML, Stephenson AH: Prostacyclin analogs stimulate receptor-mediated cAMP synthesis and ATP release from rabbit and human erythrocytes. Microcirculation. 2008 Jul;15(5):461-71. doi: 10.1080/10739680701833804. [PubMed:18574748]
  3. 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:15163595]
  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
Agonist
General Function
Zinc ion binding
Specific Function
Ligand-activated transcription factor. Receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Has a preference for poly-unsaturated fatty acids, such as gamma-lin...
Gene Name
PPARD
Uniprot ID
Q03181
Uniprot Name
Peroxisome proliferator-activated receptor delta
Molecular Weight
49902.99 Da
References
  1. Ali FY, Egan K, FitzGerald GA, Desvergne B, Wahli W, Bishop-Bailey D, Warner TD, Mitchell JA: Role of prostacyclin versus peroxisome proliferator-activated receptor beta receptors in prostacyclin sensing by lung fibroblasts. Am J Respir Cell Mol Biol. 2006 Feb;34(2):242-6. Epub 2005 Oct 20. [PubMed:16239641]
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. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]

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 un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Gotzkowsky SK, Dingemanse J, Lai A, Mottola D, Laliberte K: Lack of a pharmacokinetic interaction between oral treprostinil and bosentan in healthy adult volunteers. J Clin Pharmacol. 2010 Jul;50(7):829-34. doi: 10.1177/0091270009351173. Epub 2010 Feb 4. [PubMed:20133511]

Drug created on June 13, 2005 07:24 / Updated on October 16, 2018 08:26