ILOPROST TROMETHAMINE

Details

Stereochemistry	EPIMERIC
Molecular Formula	C22H32O4.C4H11NO3
Molecular Weight	481.6221
Optical Activity	UNSPECIFIED
Defined Stereocenters	5 / 6
E/Z Centers	2
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

NC(CO)(CO)CO.[H][C@]12C[C@@H](O)[C@H](\C=C\[C@@H](O)C(C)CC#CC)[C@@]1([H])C\C(C2)=C\CCCC(O)=O

InChI

InChIKey=KZSSWXACMCYLBM-RMWNCEGRSA-N

InChI=1S/C22H32O4.C4H11NO3/c1-3-4-7-15(2)20(23)11-10-18-19-13-16(8-5-6-9-22(25)26)12-17(19)14-21(18)24;5-4(1-6,2-7)3-8/h8,10-11,15,17-21,23-24H,5-7,9,12-14H2,1-2H3,(H,25,26);6-8H,1-3,5H2/b11-10+,16-8+;/t15?,17-,18+,19-,20+,21+;/m0./s1

HIDE SMILES / InChI

Description
Sources: http://www.drugbank.ca/drugs/DB01088
Curator's Comment: Description was created based on several sources, including http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021779s006lbl.pdf

Iloprost 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. Used for the treatment of pulmonary arterial hypertension.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Prostanoid IP receptor 18 Target ID: CHEMBL1995 Sources: http://www.drugbank.ca/drugs/DB01088	Agonist 2678		3.9 nM [Ki]
Prostanoid EP1 receptor 14 Target ID: CHEMBL1811 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22480736	Agonist 2678		1.1 nM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Pulmonary arterial hypertension 35 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021779s006lbl.pdf	Primary		Approved 8429	Ventavis Approved Use Ventavis is indicated for the treatment of pulmonary arterial hypertension (WHO Group I) in patients with NYHA Class III or IV symptoms. Launch Date 2004

C_max

Value	Dose	Analyte	Population
135 pg/mL REVIEW https://www.ema.europa.eu/en/documents/scientific-discussion/ventavis-epar-scientific-discussion_en.pdf	3 ng/kg/min other, intravenous dose: 3 ng/kg/min route of administration: Intravenous experiment type: OTHER co-administered:	ILOPROST serum	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
157 pg/mL REVIEW https://www.ema.europa.eu/en/documents/scientific-discussion/ventavis-epar-scientific-discussion_en.pdf	5 μg single, respiratory dose: 5 μg route of administration: Respiratory experiment type: SINGLE co-administered:	ILOPROST serum	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
251 pg/mL REVIEW https://www.ema.europa.eu/en/documents/scientific-discussion/ventavis-epar-scientific-discussion_en.pdf	1 μg/kg bw single, oral dose: 1 μg/kg bw route of administration: Oral experiment type: SINGLE co-administered:	ILOPROST serum	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Analyte	Population
119 pg × h/mL REVIEW https://www.ema.europa.eu/en/documents/scientific-discussion/ventavis-epar-scientific-discussion_en.pdf	3 ng/kg/min other, intravenous dose: 3 ng/kg/min route of administration: Intravenous experiment type: OTHER co-administered:	ILOPROST serum	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
47.8 pg × h/mL REVIEW https://www.ema.europa.eu/en/documents/scientific-discussion/ventavis-epar-scientific-discussion_en.pdf	5 μg single, respiratory dose: 5 μg route of administration: Respiratory experiment type: SINGLE co-administered:	ILOPROST serum	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
144 pg × h/mL REVIEW https://www.ema.europa.eu/en/documents/scientific-discussion/ventavis-epar-scientific-discussion_en.pdf	1 μg/kg bw single, oral dose: 1 μg/kg bw route of administration: Oral experiment type: SINGLE co-administered:	ILOPROST serum	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
7.91 min REVIEW https://www.ema.europa.eu/en/documents/scientific-discussion/ventavis-epar-scientific-discussion_en.pdf	5 μg single, respiratory dose: 5 μg route of administration: Respiratory experiment type: SINGLE co-administered:		ILOPROST serum	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
40% REVIEW https://www.ema.europa.eu/en/documents/scientific-discussion/ventavis-epar-scientific-discussion_en.pdf	3 ng/kg/min other, intravenous dose: 3 ng/kg/min route of administration: Intravenous experiment type: OTHER co-administered:		ILOPROST serum	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
4.4 ng/kg/min 1 times / day multiple, intravenous (mean) MTD Dose: 4.4 ng/kg/min, 1 times / day Route: intravenous Route: multiple Dose: 4.4 ng/kg/min, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/7524508 Page: p.1531	unhealthy, 14-55 n = 5 Health Status: unhealthy Condition: Pulmonary hypertension Age Group: 14-55 Sex: M+F Population Size: 5 Sources: https://pubmed.ncbi.nlm.nih.gov/7524508 Page: p.1531	Sources: https://pubmed.ncbi.nlm.nih.gov/7524508 Page: p.1531
150 ug 2 times / day multiple, oral MTD Dose: 150 ug, 2 times / day Route: oral Route: multiple Dose: 150 ug, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/7538285 Page: p.197	unhealthy, 47-57 n = 32 Health Status: unhealthy Condition: Raynaud's syndrome Age Group: 47-57 Sex: M+F Population Size: 32 Sources: https://pubmed.ncbi.nlm.nih.gov/7538285 Page: p.197	Disc. AE: Headache... AEs leading to discontinuation/dose reduction: Headache Sources: https://pubmed.ncbi.nlm.nih.gov/7538285 Page: p.197
20 ug 24 times / day multiple, respiratory Highest studied dose Dose: 20 ug, 24 times / day Route: respiratory Route: multiple Dose: 20 ug, 24 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/21962419 Page: p.816	unhealthy, 59.14+/-8.24 n = 7 Health Status: unhealthy Condition: Pulmonary hypertension Age Group: 59.14+/-8.24 Sex: M+F Population Size: 7 Sources: https://pubmed.ncbi.nlm.nih.gov/21962419 Page: p.816	Sources: https://pubmed.ncbi.nlm.nih.gov/21962419 Page: p.816
300 ug 2 times / day multiple, oral Highest studied dose Dose: 300 ug, 2 times / day Route: oral Route: multiple Dose: 300 ug, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/9349930	unhealthy n = 12 Health Status: unhealthy Condition: Thromboangiitis obliterans Population Size: 12 Sources: https://pubmed.ncbi.nlm.nih.gov/9349930	Sources: https://pubmed.ncbi.nlm.nih.gov/9349930
5 ug 9 times / day multiple, respiratory Recommended Dose: 5 ug, 9 times / day Route: respiratory Route: multiple Dose: 5 ug, 9 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021779s014lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Pulmonary arterial hypertension Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021779s014lbl.pdf Page: p.1	Disc. AE: Syncope hypotensive, Pulmonary venous hypertension... AEs leading to discontinuation/dose reduction: Syncope hypotensive Pulmonary venous hypertension Bronchospasm Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021779s014lbl.pdf Page: p.1

AEs

AE	Significance	Dose	Population
Headache	Disc. AE	150 ug 2 times / day multiple, oral MTD Dose: 150 ug, 2 times / day Route: oral Route: multiple Dose: 150 ug, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/7538285 Page: p.197	unhealthy, 47-57 n = 32 Health Status: unhealthy Condition: Raynaud's syndrome Age Group: 47-57 Sex: M+F Population Size: 32 Sources: https://pubmed.ncbi.nlm.nih.gov/7538285 Page: p.197
Bronchospasm	Disc. AE	5 ug 9 times / day multiple, respiratory Recommended Dose: 5 ug, 9 times / day Route: respiratory Route: multiple Dose: 5 ug, 9 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021779s014lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Pulmonary arterial hypertension Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021779s014lbl.pdf Page: p.1
Pulmonary venous hypertension	Disc. AE	5 ug 9 times / day multiple, respiratory Recommended Dose: 5 ug, 9 times / day Route: respiratory Route: multiple Dose: 5 ug, 9 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021779s014lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Pulmonary arterial hypertension Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021779s014lbl.pdf Page: p.1
Syncope hypotensive	Disc. AE	5 ug 9 times / day multiple, respiratory Recommended Dose: 5 ug, 9 times / day Route: respiratory Route: multiple Dose: 5 ug, 9 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021779s014lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Pulmonary arterial hypertension Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021779s014lbl.pdf Page: p.1

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737 inhibitor 1587	substrate 1037 inhibitor 1767	substrate 1217 inhibitor 1852

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1524 CYP2A6 707 CYP2C8 911 CYP2C19 1478 CYP2E1 882	CYP1A2 1054 CYP2C19 991 CYP2A6 543 CYP2C8 693 CYP2E1 667	P-gp 257 BCRP 75

Drug as perpetrator

Target	Modality	Activity
CYP2C8 965	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-779_Ventavis_biopharmr_P2.pdf#page=25 Page: 25,36	low [IC50 195.2 uM]
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-779_Ventavis_biopharmr_P2.pdf#page=25 Page: 25,36	low [IC50 55.6 uM]
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-779_Ventavis_biopharmr_P2.pdf#page=25 Page: 25,36	low [IC50 >100 uM]
CYP2A6 739	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-779_Ventavis_biopharmr_P2.pdf#page=25 Page: 25,36	low [IC50 >100 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-779_Ventavis_biopharmr_P2.pdf#page=25 Page: 25,36	low [IC50 >100 uM]
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-779_Ventavis_biopharmr_P2.pdf#page=25 Page: 25,36	low [IC50 >100 uM]
CYP2E1 970	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-779_Ventavis_biopharmr_P2.pdf#page=25 Page: 25,36	low [IC50 >100 uM]
CYP3A4 1925	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-779_Ventavis_biopharmr_P2.pdf#page=25 Page: 25,36	low [IC50 >100 uM]
BCRP 773	inducer 1573 Sources: https://pubmed.ncbi.nlm.nih.gov/22845665/	yes
P-gp 1650	inducer 1573 Sources: https://pubmed.ncbi.nlm.nih.gov/22845665/	yes

Drug as victim

Target	Modality	Activity
CYP1A2 1054	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-779_Ventavis_biopharmr_P2.pdf#page=24 Page: 24.0	likely
CYP2C19 991	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-779_Ventavis_biopharmr_P2.pdf#page=24 Page: 24.0	likely
CYP2C9 1037	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-779_Ventavis_biopharmr_P2.pdf#page=24 Page: 24.0	likely
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-779_Ventavis_biopharmr_P2.pdf#page=24 Page: 24.0	likely
CYP2A6 543	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-779_Ventavis_biopharmr_P2.pdf#page=24 Page: 24.0	no
CYP2C8 693	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-779_Ventavis_biopharmr_P2.pdf#page=24 Page: 24.0	no
CYP2D6 1217	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-779_Ventavis_biopharmr_P2.pdf#page=24 Page: 24.0	no
CYP2E1 667	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-779_Ventavis_biopharmr_P2.pdf#page=24 Page: 24.0	no

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:63916	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:63916
ChemicalBook	CB0775438	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB0775438
ChemicalBook	CB3775439	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB3775439
MolPort	MolPort-023-276-312	https://www.molport.com/shop/molecule-link/MolPort-023-276-312
eMolecules	27315410	https://www.emolecules.com/cgi-bin/more?vid=27315410

PubMed

Title	Date	PubMed
A comparative study of PGI2 mimetics used clinically on the vasorelaxation of human pulmonary arteries and veins, role of the DP-receptor.	2013 Dec	23850788
Effective prevention of pseudothrombocytopenia in feline blood samples with the prostaglandin I2 analogue Iloprost.	2015 Aug 6	26245701
Iloprost supports early development of in vitro-produced porcine embryos through activation of the phosphatidylinositol 3-kinase/AKT signalling pathway.	2017 Jul	27279419

Patents

Sample Use Guides

In Vivo Use Guide

Ventavis is intended to be inhaled using either of two pulmonary drug delivery devices: the I-neb™ AAD® System or the Prodose® AAD® System. The first inhaled dose should be 2.5 mcg (as delivered at the mouthpiece). If this dose is well tolerated, dosing should be increased to 5.0 mcg and maintained at that dose; otherwise maintain the dose at 2.5 mcg. Ventavis should be taken 6 to 9 times per day (no more than once every 2 hours) during waking hours, according to individual need and tolerability. The maximum daily dose evaluated in clinical studies was 45 mcg (5 mcg 9 times per day).

Route of Administration: Respiratory

In Vitro Use Guide

Phosphatidylinositol 3-kinase (PI3K)/AKT signalling pathway was significantly activated by iloprost supplementation of early porcine embryos in a concentration-dependent manner (10-1000 nM)

Name

Type

Language

ILOPROST TROMETHAMINE

Common Name

English

Iloprost trometamol [WHO-DD]

Common Name

English

PENTANOIC ACID, 5-((3AS,4R,5R,6AS)-HEXAHYDRO-5-HYDROXY-4-((1E,3S)-3-HYDROXY-4-METHYL-1-OCTEN-6-YNYL)-2(1H)-PENTALENYLIDENE)-, (5E)-, COMPD. WITH 2-AMINO-2-(HYDROXYMETHYL)-1,3-PROPANEDIOL (1:1)

Common Name

English

ILOPROST TROMETHAMINE [MI]

Common Name

English

ILOPROST TROMETAMOL

Common Name

English

CILOPROST TROMETAMOL

Common Name

English

TROMETAMOL ILOPROST

Common Name

English

Code System Code Type Description

SMS_ID

100000090093