Details of the Drug

General Information of Drug (ID: DMP79A1)

Drug Name

Macitentan

Synonyms

Macitentan; 441798-33-0; Opsumit; ACT-064992; ACT 064992; UNII-Z9K9Y9WMVL; ACT064992; Z9K9Y9WMVL; N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-propylsulfamide; N-(5-(4-Bromophenyl)-6-(2-((5-bromo-2-pyrimidinyl)oxy)ethoxy)-4-pyrimidinyl)-N'-propylsulfamide; CHEBI:76607; Actelion-1; Macitentan [USAN:INN]; macitentanum; zlchem 5; Opsumit (TN); Macitentan (JAN/USAN); (non-labelled)Macitentan-d7; MLS006011174; C19H20Br2N6O4S; SCHEMBL1445625; GTPL7352; CHEMBL2103873; ZLA0005; EX-A544; DTXSID50196063

Indication

Disease Entry	ICD 11	Status	REF
Cardiovascular disease	BA00-BE2Z	Approved	[1], [2], [3]

Drug Type

Small molecular drug

Structure

3D MOL

2D MOL

#Ro5 Violations (Lipinski): 2

Molecular Weight (mw)

588.3

Topological Polar Surface Area (xlogp)

3.7

Rotatable Bond Count (rotbonds)

Hydrogen Bond Donor Count (hbonddonor)

Hydrogen Bond Acceptor Count (hbondacc)

ADMET Property

Bioavailability: The bioavailability of drug is 10-90% [4]
Elimination: Eliminated 50% through urine and 24% through feces. Of the 50% excreted through the urine, none of the recovered dose was in the form of the parent drug nor the active metabolite [5]
Half-life: The concentration or amount of drug in body reduced by one-half in 16 hours [5]
Metabolism: The drug is metabolized via the CYP3A4 [6]
Vd: The volume of distribution (Vd) of drug is 40-50 L [5]

Chemical Identifiers

Formula: C19H20Br2N6O4S
IUPAC Name: 5-(4-bromophenyl)-6-[2-(5-bromopyrimidin-2-yl)oxyethoxy]-N-(propylsulfamoyl)pyrimidin-4-amine
Canonical SMILES: CCCNS(=O)(=O)NC1=C(C(=NC=N1)OCCOC2=NC=C(C=N2)Br)C3=CC=C(C=C3)Br
InChI: InChI=1S/C19H20Br2N6O4S/c1-2-7-26-32(28,29)27-17-16(13-3-5-14(20)6-4-13)18(25-12-24-17)30-8-9-31-19-22-10-15(21)11-23-19/h3-6,10-12,26H,2,7-9H2,1H3,(H,24,25,27)
InChIKey: JGCMEBMXRHSZKX-UHFFFAOYSA-N

Cross-matching ID

PubChem CID: 16004692
ChEBI ID: CHEBI:76607
CAS Number: 441798-33-0
DrugBank ID: DB08932
TTD ID: D0S7JH
INTEDE ID: DR0998
ACDINA ID: D00382

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Endothelin A receptor (EDNRA)	TTKRD0G	EDNRA_HUMAN	Modulator	[2]
Endothelin B receptor (EDNRB)	TT3ZTGU	EDNRB_HUMAN	Modulator	[2]

------------------------------------------------------------------------------------

Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 3A4 (CYP3A4)_{Main DME}	DE4LYSA	CP3A4_HUMAN	Substrate	[7]
Mephenytoin 4-hydroxylase (CYP2C19)_{Main DME}	DEGTFWK	CP2CJ_HUMAN	Substrate	[7]

------------------------------------------------------------------------------------

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This Drug

Molecular Expression Atlas of This Drug

The Studied Disease

Cardiovascular disease

ICD Disease Classification

BA00-BE2Z

Molecule Name	Molecule Type	Gene Name	p-value	Fold-Change	Z-score
Endothelin A receptor (EDNRA)	DTT	EDNRA	3.19E-05	-2.69	-1.71
Mephenytoin 4-hydroxylase (CYP2C19)	DME	CYP2C19	1.39E-02	-2.78E-01	-5.67E-01
Cytochrome P450 3A4 (CYP3A4)	DME	CYP3A4	1.10E-01	-1.23E-01	-2.88E-01

Molecular Expression Atlas (MEA)

MEA Detail

Jump to Detail Molecular Expression Atlas of This Drug

Drug-Drug Interaction (DDI) Information of This Drug

Coadministration of a Drug Treating the Disease Different from Macitentan (Comorbidity)

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Remdesivir	DMBFZ6L	Moderate	Increased risk of hepatotoxicity by the combination of Macitentan and Remdesivir.	1D6YCoronavirus Disease 2019 [1D6YCoronavirus Disease 2019]	[45]
Ivosidenib	DM8S6T7	Moderate	Increased metabolism of Macitentan caused by Ivosidenib mediated induction of CYP450 enzyme.	Acute myeloid leukaemia [2A60]	[46]
Arn-509	DMT81LZ	Major	Increased metabolism of Macitentan caused by Arn-509 mediated induction of CYP450 enzyme.	Acute myeloid leukaemia [2A60]	[46]
Troleandomycin	DMUZNIG	Major	Decreased metabolism of Macitentan caused by Troleandomycin mediated inhibition of CYP450 enzyme.	Bacterial infection [1A00-1C4Z]	[47]
Pexidartinib	DMS2J0Z	Major	Increased risk of hepatotoxicity by the combination of Macitentan and Pexidartinib.	Bone/articular cartilage neoplasm [2F7B]	[48]
Tucatinib	DMBESUA	Major	Decreased metabolism of Macitentan caused by Tucatinib mediated inhibition of CYP450 enzyme.	Breast cancer [2C60-2C6Y]	[47]
Palbociclib	DMD7L94	Moderate	Decreased metabolism of Macitentan caused by Palbociclib mediated inhibition of CYP450 enzyme.	Breast cancer [2C60-2C6Y]	[47]
Lumacaftor	DMCLWDJ	Major	Increased metabolism of Macitentan caused by Lumacaftor mediated induction of CYP450 enzyme.	Cystic fibrosis [CA25]	[46]
MK-8228	DMOB58Q	Moderate	Decreased metabolism of Macitentan caused by MK-8228 mediated inhibition of CYP450 enzyme.	Cytomegaloviral disease [1D82]	[47]
Stiripentol	DMMSDOY	Moderate	Decreased metabolism of Macitentan caused by Stiripentol mediated inhibition of CYP450 enzyme.	Epilepsy/seizure [8A61-8A6Z]	[47]
Eslicarbazepine	DMZREFQ	Moderate	Increased metabolism of Macitentan caused by Eslicarbazepine mediated induction of CYP450 enzyme.	Epilepsy/seizure [8A61-8A6Z]	[46]
Cannabidiol	DM0659E	Moderate	Increased risk of hepatotoxicity by the combination of Macitentan and Cannabidiol.	Epileptic encephalopathy [8A62]	[49]
Tazemetostat	DMWP1BH	Moderate	Increased metabolism of Macitentan caused by Tazemetostat mediated induction of CYP450 enzyme.	Follicular lymphoma [2A80]	[46]
Cobicistat	DM6L4H2	Major	Decreased metabolism of Macitentan caused by Cobicistat mediated inhibition of CYP450 enzyme.	Human immunodeficiency virus disease [1C60-1C62]	[47]
Berotralstat	DMWA2DZ	Moderate	Decreased metabolism of Macitentan caused by Berotralstat mediated inhibition of CYP450 enzyme.	Innate/adaptive immunodeficiency [4A00]	[47]
Suvorexant	DM0E6S3	Moderate	Decreased metabolism of Macitentan caused by Suvorexant mediated inhibition of CYP450 enzyme.	Insomnia [7A00-7A0Z]	[47]
Ceritinib	DMB920Z	Major	Decreased metabolism of Macitentan caused by Ceritinib mediated inhibition of CYP450 enzyme.	Lung cancer [2C25]	[47]
PF-06463922	DMKM7EW	Moderate	Increased metabolism of Macitentan caused by PF-06463922 mediated induction of CYP450 enzyme.	Lung cancer [2C25]	[46]
Selpercatinib	DMZR15V	Moderate	Decreased metabolism of Macitentan caused by Selpercatinib mediated inhibition of CYP450 enzyme.	Lung cancer [2C25]	[47]
Calaspargase pegol	DMQZBXI	Moderate	Increased risk of hepatotoxicity by the combination of Macitentan and Calaspargase pegol.	Malignant haematopoietic neoplasm [2B33]	[50]
Idelalisib	DM602WT	Major	Decreased metabolism of Macitentan caused by Idelalisib mediated inhibition of CYP450 enzyme.	Mature B-cell leukaemia [2A82]	[47]
IPI-145	DMWA24P	Moderate	Decreased metabolism of Macitentan caused by IPI-145 mediated inhibition of CYP450 enzyme.	Mature B-cell leukaemia [2A82]	[47]
Fedratinib	DM4ZBK6	Moderate	Decreased metabolism of Macitentan caused by Fedratinib mediated inhibition of CYP450 enzyme.	Myeloproliferative neoplasm [2A20]	[47]
Netupitant	DMEKAYI	Moderate	Decreased metabolism of Macitentan caused by Netupitant mediated inhibition of CYP450 enzyme.	Nausea/vomiting [MD90]	[47]
Rucaparib	DM9PVX8	Moderate	Decreased metabolism of Macitentan caused by Rucaparib mediated inhibition of CYP450 enzyme.	Ovarian cancer [2C73]	[47]
Abametapir	DM2RX0I	Moderate	Decreased metabolism of Macitentan caused by Abametapir mediated inhibition of CYP450 enzyme.	Pediculosis [1G00]	[51]
Lefamulin	DME6G97	Moderate	Decreased metabolism of Macitentan caused by Lefamulin mediated inhibition of CYP450 enzyme.	Pneumonia [CA40]	[52]
Voxelotor	DMCS6M5	Moderate	Decreased metabolism of Macitentan caused by Voxelotor mediated inhibition of CYP450 enzyme.	Sickle-cell disorder [3A51]	[47]
Telotristat ethyl	DMDIYFZ	Moderate	Increased metabolism of Macitentan caused by Telotristat ethyl mediated induction of CYP450 enzyme.	Small intestine developmental anomaly [DA90]	[49]
Larotrectinib	DM26CQR	Moderate	Decreased metabolism of Macitentan caused by Larotrectinib mediated inhibition of CYP450 enzyme.	Solid tumour/cancer [2A00-2F9Z]	[47]
LEE011	DMMX75K	Moderate	Decreased metabolism of Macitentan caused by LEE011 mediated inhibition of CYP450 enzyme.	Solid tumour/cancer [2A00-2F9Z]	[47]
Pitolisant	DM8RFNJ	Moderate	Increased metabolism of Macitentan caused by Pitolisant mediated induction of CYP450 enzyme.	Somnolence [MG42]	[49]
Fostamatinib	DM6AUHV	Moderate	Decreased metabolism of Macitentan caused by Fostamatinib mediated inhibition of CYP450 enzyme.	Thrombocytopenia [3B64]	[53]
Elagolix	DMB2C0E	Moderate	Increased metabolism of Macitentan caused by Elagolix mediated induction of CYP450 enzyme.	Uterine fibroid [2E86]	[46]
-----------


⏷ Show the Full List of 34 DDI Information of This Drug

Drug Inactive Ingredient(s) (DIG) and Formulation(s) of This Drug

DIG

DIG Name	DIG ID	PubChem CID	Functional Classification
Lactose monohydrate	E00393	104938	Binding agent; Diluent; Dry powder inhaler carrier; Lyophilization aid
Magnesium stearate	E00208	11177	lubricant
Polysorbate 80	E00665	Not Available	Dispersing agent; Emollient; Emulsifying agent; Plasticizing agent; Solubilizing agent; Surfactant; Suspending agent
Soybean lecithin	E00637	Not Available	Other agent
Talc	E00520	16211421	Anticaking agent; Diluent; Glidant; lubricant
Titanium dioxide	E00322	26042	Coating agent; Colorant; Opacifying agent
--------------------


⏷ Show the Full List of 6 Pharmaceutical Excipients of This Drug

Pharmaceutical Formulation

Formulation Name	Drug Dosage	Dosage Form	Route
Macitentan 10 mg tablet	10 mg	Oral Tablet	Oral

Jump to Detail Pharmaceutical Formulation Page of This Drug

References

1	URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7352).
2	Radium 223 dichloride for prostate cancer treatment. Drug Des Devel Ther. 2017 Sep 6;11:2643-2651.
3	Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
4	Lasix Oral (furosemide) Product Monograph
5	DPD Approved Drug Products: Opsynvi (tadalafil/macitentan) combination tablets
6	Pavan-Langston D, Nelson DJ: Intraocular penetration of trifluridine. Am J Ophthalmol. 1979 Jun;87(6):814-8.
7	Investigation of the effects of ketoconazole on the pharmacokinetics of macitentan, a novel dual endothelin receptor antagonist, in healthy subjects. Clin Pharmacokinet. 2013 Aug;52(8):685-92.
8	Expression levels and activation of a PXR variant are directly related to drug resistance in osteosarcoma cell lines. Cancer. 2007 Mar 1;109(5):957-65.
9	Contribution of human hepatic cytochrome P450 isoforms to regioselective hydroxylation of steroid hormones. Xenobiotica. 1998 Jun;28(6):539-47.
10	Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther. 2004 Sep;310(3):1062-75.
11	Isoform-specific regulation of cytochromes P450 expression by estradiol and progesterone. Drug Metab Dispos. 2013 Feb;41(2):263-9.
12	Metabolic interactions between acetaminophen (paracetamol) and two flavonoids, luteolin and quercetin, through in-vitro inhibition studies. J Pharm Pharmacol. 2017 Dec;69(12):1762-1772.
13	Potent mechanism-based inhibition of CYP3A4 by imatinib explains its liability to interact with CYP3A4 substrates. Br J Pharmacol. 2012 Apr;165(8):2787-98.
14	Effects of morin on the pharmacokinetics of etoposide in rats. Biopharm Drug Dispos. 2007 Apr;28(3):151-6.
15	The metabolism of zidovudine by human liver microsomes in vitro: formation of 3'-amino-3'-deoxythymidine. Biochem Pharmacol. 1994 Jul 19;48(2):267-76.
16	Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.
17	High-dose rabeprazole/amoxicillin therapy as the second-line regimen after failure to eradicate H. pylori by triple therapy with the usual doses of a proton pump inhibitor, clarithromycin and amoxicillin. Hepatogastroenterology. 2003 Nov-Dec;50(54):2274-8.
18	Progesterone and testosterone hydroxylation by cytochromes P450 2C19, 2C9, and 3A4 in human liver microsomes. Arch Biochem Biophys. 1997 Oct 1;346(1):161-9.
19	Cytochrome P450 pharmacogenetics and cancer. Oncogene. 2006 Mar 13;25(11):1679-91.
20	CYP2C19*17 is associated with decreased breast cancer risk. Breast Cancer Res Treat. 2009 May;115(2):391-6.
21	Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
22	Cytochromes of the P450 2C subfamily are the major enzymes involved in the O-demethylation of verapamil in humans. Naunyn Schmiedebergs Arch Pharmacol. 1995 Dec;353(1):116-21.
23	Diclofenac and its derivatives as tools for studying human cytochromes P450 active sites: particular efficiency and regioselectivity of P450 2Cs. Biochemistry. 1999 Oct 26;38(43):14264-70.
24	A mechanistic approach to antiepileptic drug interactions. Ann Pharmacother. 1998 May;32(5):554-63.
25	Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver. Gastroenterology. 2001 Feb;120(2):525-33.
26	Possible involvement of multiple human cytochrome P450 isoforms in the liver metabolism of propofol. Br J Anaesth. 1998 Jun;80(6):788-95.
27	Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
28	Clinical pipeline report, company report or official report of GlaxoSmithKline (2009).
29	Influence of endothelin receptor antagonists on myocardial protein kinase C isoforms in uraemic cardiomyopathy. Clin Sci (Lond). 2002 Aug;103 Suppl 48:276S-279S.
30	Effects of a selective ET(A)-receptor antagonist, atrasentan (ABT-627), in murine models of allergic asthma: demonstration of mouse strain specificity. Clin Sci (Lond). 2002 Aug;103 Suppl 48:367S-370S.
31	Effects of the selective endothelin A (ET(A)) receptor antagonist Clazosentan on cerebral perfusion and cerebral oxygenation following severe subar... Acta Neurochir (Wien). 2007;149(9):911-8; discussion 918.
32	Designed multiple ligands. An emerging drug discovery paradigm. J Med Chem. 2005 Oct 20;48(21):6523-43.
33	Pfizer. Product Development Pipeline. March 31 2009.
34	Endothelin ETA receptor blockade with darusentan increases sodium and potassium excretion in aging rats. J Cardiovasc Pharmacol. 2006 Mar;47(3):456-62.
35	Endothelin in heart failure: a promising therapeutic target Heart. 1997 Feb;77(2):93-4.
36	Reduction of bFGF-induced smooth muscle cell proliferation and endothelin receptor mRNA expression by mevastatin and atorvastatin. Biochem Pharmacol. 2002 Aug 1;64(3):497-505.
37	BQ788, an endothelin ET(B) receptor antagonist, attenuates stab wound injury-induced reactive astrocytes in rat brain. Glia. 1999 May;26(3):268-71.
38	Reversal of established responses to endothelin-1 in vivo and in vitro by the endothelin receptor antagonists, BQ-123 and PD 145065. Br J Pharmacol. 1994 May;112(1):207-13.
39	Clinical pipeline report, company report or official report of Spectrum Phamaceuticals (2009).
40	Pharmacological properties of J-104132 (L-753,037), a potent, orally active, mixed ETA/ETB endothelin receptor antagonist. J Pharmacol Exp Ther. 1999 Jun;289(3):1262-70.
41	Enrasentan, an antagonist of endothelin receptors. Cardiovasc Drug Rev. 2003 Spring;21(1):1-16.
42	Effects of the endothelin receptor antagonist, SB 209670, on circulatory failure and organ injury in endotoxic shock in the anaesthetized rat. Br J Pharmacol. 1996 May;118(1):198-204.
43	IRL 2500: A potent ETB selective endothelin antagonist, Bioorg. Med. Chem. Lett. 6(19):2323-2328 (1996).
44	Human optic nerve head astrocytes as a target for endothelin-1. Invest Ophthalmol Vis Sci. 2002 Aug;43(8):2704-13.
45	Cerner Multum, Inc. "Australian Product Information.".
46	Bruderer S, Aanismaa P, Homery MC, et al. "Effect of cyclosporine and rifampin on the pharmacokinetics of macitentan, a tissue-targeting dual endothelin receptor antagonist." AAPS J 14 (2012): 68-78. [PMID: 22189899]
47	Product Information. Opsumit (macitentan). Actelion Pharmaceuticals US Inc, South San Francisco, CA.
48	Product Information. Turalio (pexidartinib). Daiichi Sankyo, Inc., Parsippany, NJ.
49	Cerner Multum, Inc. "UK Summary of Product Characteristics.".
50	Al-Nawakil C, Willems L, Mauprivez C, et.al "Successful treatment of l-asparaginase-induced severe acute hepatotoxicity using mitochondrial cofactors." Leuk Lymphoma 55 (2014): 1670-4. [PMID: 24090500]
51	Product Information. Xeglyze (abametapir topical). Dr. Reddy's Laboratories Inc, Upper Saddle River, NJ.
52	Product Information. Xenleta (lefamulin). Nabriva Therapeutics US, Inc., King of Prussia, PA.
53	Product Information. Tavalisse (fostamatinib). Rigel Pharmaceuticals, South San Francisco, CA.