{ { Drugbox
| image = Macitentan skeletal.svg
| alt =
| caption =
| tradename = Opsumit
| Drugs.com =
| MedlinePlus = a615033
| licence_EU = yes
| DailyMedID = Macitentan
| pregnancy_AU = X
| pregnancy_category=
| routes_of_administration = By mouth
| ATCvet =
| ATC_prefix = C02
| ATC_suffix = KX04
| ATC_supplemental =
| legal_AU = S4
| legal_AU_comment =
| legal_CA =
| legal_UK =
| legal_US = Rx-only
| legal_US_comment =
| bioavailability =
| protein_bound =
| metabolism = Hydrolysis, oxidation (CYP3A4) | elimination_half-life = | excretion = 2/3 urine, 1/3 faeces
| CAS_number = 441798-33-0
| PubChem = 16004692
| DrugBank = DB08932
| ChemSpiderID = 13134960
| UNII_Ref =
| UNII = Z9K9Y9WMVL
| KEGG = D10135
| ChEBI = 76607
| ChEMBL = 2103873
| synonyms = ACT-064992
| IUPAC_name = N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-''N-propylsulfamide | C=19 | H=20 | Br=2 | N=6 | O=4 | S=1 | smiles = Brc1ccc(cc1)c3c(ncnc3OCCOc2ncc(Br)cn2)NS(=O)(=O)NCCC | StdInChI = 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) | StdInChIKey = JGCMEBMXRHSZKX-UHFFFAOYSA-N }}Macitentan, sold under the brand name Opsumit''', is an endothelin receptor antagonist (ERA) developed by Actelion and approved for the treatment of pulmonary arterial hypertension (PAH). The other two ERAs marketed as of 2014 are bosentan and ambrisentan. Macitentan is a dual ERA, meaning that it acts as an antagonist of two endothelin (ET) receptor subtypes, ETA and ETB. However, macitentan has a 50-fold increased selectivity for the ETA subtype compared to the ETB subtype. The drug received approval from the U.S. Food and Drug Administration (FDA) on October 13, 2013.
Macitentan is available as a generic medication in the United States as of April 2021.
Adverse effects
The FDA has issued a black box warning for macitentan for embryo-fetal toxicity. It is only available to females in the U.S through a risk evaluation and mitigation strategy (REMS) program.
Mechanism of action
Endothelin and endothelin receptors
Endothelin (ET) is an extremely potent blood vessel constricting substance that is secreted by endothelial cells. In the lungs, the most common ET form released is ET-1. ET-1 release can occur through both constitutive and non-constitutive pathways. Upon release, ET-1 can bind to the ET receptors that are expressed on arterial smooth muscle cells and fibroblasts in the lungs. ET receptors are G protein coupled receptors and, when activated, lead to an increase in intracellular calcium levels via the Gαq signaling pathway. There are two receptor subtypes that endothelin will bind to: ETA and ETB. ETA is associated with cell growth and vasoconstriction while ETB is responsible for anti-proliferation of cells, vasodilation and ET-1 clearance. The rise in intracellular calcium leads to contraction of the arterial smooth muscle, as well as vascular remodelling due to cell proliferation. Prolonged constriction and fibrosis are factors in the pathogenesis of PAH.
Role of macitentan
Macitentan blocks the ET1-dependent rise in intracellular calcium by inhibiting the binding of ET-1 to ET receptors. Blocking of the ETA receptor subtype seems to be of more importance in the treatment of PAH than blocking of ETB, likely because there are higher numbers of ETA receptors than ETB receptors in pulmonary arterial smooth muscle cells. The blocking of Endothelin 1 leads to vasodilation and decreases the proliferation of cells in the vessels of the artries which contributes to the narrowing and leads to the pulmonary arterial hypertension.