Macitentan
Explore a selection of our essential drug information below, or:
Identification
- Summary
Macitentan is an endothelin receptor antagonist used to manage pulmonary arterial hypertension to delay disease progression.
- Brand Names
- Opsumit
- Generic Name
- Macitentan
- DrugBank Accession Number
- DB08932
- Background
Macitentan is a dual endothelin receptor antagonist used in the treatment of pulmonary arterial hypertension (PAH).5 It was first approved by the FDA in 2013. Macitentan differs from its predecessor bosentan in part due to its lower risk of hepatotoxicity.
A combination product (Opsynvi) comprising macitentan and tadalafil was approved in Canada in October 2021 for the treatment of PAH.6 It was subsequently approved by the FDA in March 2024.7
- Type
- Small Molecule
- Groups
- Approved
- Structure
- Weight
- Average: 588.273
Monoisotopic: 585.963349142 - Chemical Formula
- C19H20Br2N6O4S
- Synonyms
- Macitentán
- Macitentan
- Macitentanum
- External IDs
- ACT 064992
- ACT-064992
- ACT064992
Pharmacology
- Indication
Macitentan, alone or in combination with tadalafil, is indicated for the treatment of pulmonary arterial hypertension (PAH; WHO Group 1) in adult patients of WHO functional class II to III .5,6,7
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Used in combination to treat Pulmonary arterial hypertension (pah) Combination Product in combination with: Tadalafil (DB00820) •••••••••••• ••••• ••• •••••••••• ••••• •••••• •••••• Used in combination to treat Pulmonary arterial hypertension (pah) Combination Product in combination with: Tadalafil (DB00820) •••••••••••• ••••• ••• •••••••••• ••••• •••••• •••••• Treatment of Pulmonary arterial hypertension (pah) •••••••••••• ••••• ••• •••••••••• ••••• •••••• •••••• - Contraindications & Blackbox Warnings
- Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API
- Pharmacodynamics
Macitentan acts primarily by reducing vasoconstriction and cell proliferation due to endothelin overexpression.5,6
- Mechanism of action
Macitentan is an antagonist which binds to the endothelin A and B receptors (EA and EB) and blocks signaling from endothelin-1 and -2.5,6,3 Pulmonary arterial hypertension has many different mechanisms which contribute to the development of endothelial dysfunction including elevated cytosolic calcium, genetic factors, epigenetic changes, and mitochondrial dysfunction.2 The focus of macitentan's mechanism relates to the role of overexpressed endothelin from the vascular endothelium. Endothelins are released in both a constitutive fashion from secretory vesicles and in response to stimuli via Weibel-Palade storage granules.1 Endothelins bind to the EA and EB receptors, with endothelins -1 and -2 having more affinity than endothelin-3.3 Binding to the Gq coupled EA receptor triggers Ca2+ release from the sarcoplasmic reticulum of smooth muscle cells via the phospholipase C (PLC) pathway. Downstream protein kinase C activation may also contribute to increased Ca2+ sensitivity of the contractile apparatus. EA receptor activation is also known to contribute to pulmonary artery smooth muscle cell proliferation. The binding of endothelins to the EB receptors acts in opposition to EA signaling by activating the same PLC cascade in endothelial cells to activate endothelial nitric oxide synthase. The subsequent release of nitric oxide produces vasodilation through the cyclic guanosine monophosphate cascade.1 Despite the greater presence of EB receptors on endothelial cells, they are still present on smooth muscle cells and may contribute to cell proliferation through the same mechanisms as EA receptors.3 Macitentan is thought to provide its therapeutic effect primarily via blocking signaling through EA which produces both decreased vasoconstriction via reduced smooth muscle cell contractility and attenuation of the hyperproliferation of smooth muscle cells found in PAH. Blockade of EB is less likely to contribute to a therapeutic effect as this signaling is responsible for the counter-regulatory vasodilatory signal.
Target Actions Organism AEndothelin-1 receptor antagonistHumans UEndothelin receptor type B antagonistHumans - Absorption
Macitentan has a median Tmax of 8h although some studies have found up to 30h at higher doses.6,4 Although the bioavailability has not been experimentally determined, pharmacokinetic modeling has estimated it at 74%.4 Food has not been found to have a significant effect on absorption.
- Volume of distribution
Macitentan has an apparent volume of distribution of 40-50L.6,4
- Protein binding
Macitentan is >99% bound to plasma proteins, primarily to albumin and to a lesser extent α1-acid glycoprotein.6,4
- Metabolism
Macitentan undergoes oxidative depropylation of the sulfonamide moiety via CYP3A4, 2C8, 2C9, and 2C19 to form the active metabolite M6.4 The ethylene glycol moiety undergoes oxidative cleavage via CYP2C9 to the alcohol metabolite M4. M4 is oxidized to its corresponding acid, M5, then hydrolyzed to the metabolite termed m/z 324. Oxidative depropylation of a distal carbon atom via CYP2C8, 2C9, and 2C19 forms M7. Hydrolysis of both macitentan and M5 produces M3. Finally M5 may be further metabolized via hydrolysis and hydroxylation to M2 or via glucuronidation to a glucuronide metabolite, M1.
Hover over products below to view reaction partners
- Route of elimination
Eliminated 50% through urine and 24% through feces.6,4 Of the 50% excreted through the urine, none of the recovered dose was in the form of the parent drug nor the active metabolite.
- Half-life
The half-life of elimination of macitentan is 16 hours.6,4 The half-life of elimination of the active metabolite is 40-66h.
- Clearance
Clearance data was not found.
- Adverse Effects
- Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.
- Toxicity
At high doses, macitentan may produce headache, nausea, and vomiting.6 In case of overdose standard supportive measures are recommended. Hemodialysis is not expected to contribute significantly to macitentan clearance due to its high degree of plasma protein binding.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbacavir Abacavir may decrease the excretion rate of Macitentan which could result in a higher serum level. Abaloparatide Abaloparatide may increase the hypotensive activities of Macitentan. Abametapir The serum concentration of Macitentan can be increased when it is combined with Abametapir. Acebutolol Acebutolol may increase the hypotensive activities of Macitentan. Aceclofenac The therapeutic efficacy of Macitentan can be decreased when used in combination with Aceclofenac. - Food Interactions
- Take with or without food.
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Opsumit Tablet, film coated 10 mg Oral Janssen Cilag International Nv 2020-12-22 Not applicable EU Opsumit Tablet, film coated 10 mg Oral Janssen Cilag International Nv 2020-12-22 Not applicable EU Opsumit Tablet 10 mg Oral Janssen Pharmaceuticals 2014-01-15 Not applicable Canada Opsumit Tablet, film coated 10 mg Oral Janssen Cilag International Nv 2020-12-22 Not applicable EU Opsumit Tablet, film coated 10 mg/1 Oral Actelion Pharmaceuticals US, Inc. 2013-11-04 Not applicable US - Mixture Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Region Image Opsynvi Macitentan (10 mg/1) + Tadalafil (40 mg/1) Tablet, film coated Oral Actelion Pharmaceuticals US, Inc. 2024-03-22 Not applicable US Opsynvi Macitentan (10 mg/1) + Tadalafil (20 mg/1) Tablet, film coated Oral Actelion Pharmaceuticals US, Inc. 2024-03-22 Not applicable US Opsynvi Macitentan (10 mg) + Tadalafil (40 mg) Tablet Oral Janssen Pharmaceuticals 2021-11-25 Not applicable Canada
Categories
- ATC Codes
- C02KX04 — Macitentan
- C02KX — Antihypertensives for pulmonary arterial hypertension
- C02K — OTHER ANTIHYPERTENSIVES
- C02 — ANTIHYPERTENSIVES
- C — CARDIOVASCULAR SYSTEM
- Drug Categories
- Amides
- Antihypertensive Agents
- Antihypertensives for Pulmonary Arterial Hypertension
- Cytochrome P-450 CYP2C19 Substrates
- Cytochrome P-450 CYP2C8 Substrates
- Cytochrome P-450 CYP2C9 Substrates
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 Substrates
- Drugs that are Mainly Renally Excreted
- Endothelin A Receptor Antagonists
- Endothelin B Receptor Antagonists
- Endothelin Receptor Antagonists
- Sulfones
- Sulfur Compounds
- Vasodilating Agents
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as halopyrimidines. These are aromatic compounds containing a halogen atom linked to a pyrimidine ring. Pyrimidine is a 6-membered ring consisting of four carbon atoms and two nitrogen centers at the 1- and 3- ring positions.
- Kingdom
- Organic compounds
- Super Class
- Organoheterocyclic compounds
- Class
- Diazines
- Sub Class
- Pyrimidines and pyrimidine derivatives
- Direct Parent
- Halopyrimidines
- Alternative Parents
- Bromobenzenes / Alkyl aryl ethers / Sulfuric acid diamides / Imidolactams / Aryl bromides / Heteroaromatic compounds / Azacyclic compounds / Organopnictogen compounds / Organonitrogen compounds / Organobromides show 2 more
- Substituents
- Alkyl aryl ether / Aromatic heteromonocyclic compound / Aryl bromide / Aryl halide / Azacycle / Benzenoid / Bromobenzene / Ether / Halobenzene / Halopyrimidine show 14 more
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- organobromine compound, aromatic ether, pyrimidines, ring assembly, sulfamides (CHEBI:76607)
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- Z9K9Y9WMVL
- CAS number
- 441798-33-0
- InChI Key
- JGCMEBMXRHSZKX-UHFFFAOYSA-N
- 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)
- IUPAC Name
- {[5-(4-bromophenyl)-6-{2-[(5-bromopyrimidin-2-yl)oxy]ethoxy}pyrimidin-4-yl]sulfamoyl}(propyl)amine
- SMILES
- CCCNS(=O)(=O)NC1=C(C(OCCOC2=NC=C(Br)C=N2)=NC=N1)C1=CC=C(Br)C=C1
References
- Synthesis Reference
Bolli MH, Boss C, Binkert C, Buchmann S, Bur D, Hess P, Iglarz M, Meyer S, Rein J, Rey M, Treiber A, Clozel M, Fischli W, Weller T: The discovery of N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-p ropylsulfamide (Macitentan), an orally active, potent dual endothelin receptor antagonist. J Med Chem. 2012 Sep 13;55(17):7849-61. doi: 10.1021/jm3009103. Epub 2012 Aug 16. Pubmed
- General References
- Davenport AP, Hyndman KA, Dhaun N, Southan C, Kohan DE, Pollock JS, Pollock DM, Webb DJ, Maguire JJ: Endothelin. Pharmacol Rev. 2016 Apr;68(2):357-418. doi: 10.1124/pr.115.011833. [Article]
- Thenappan T, Ormiston ML, Ryan JJ, Archer SL: Pulmonary arterial hypertension: pathogenesis and clinical management. BMJ. 2018 Mar 14;360:j5492. doi: 10.1136/bmj.j5492. [Article]
- Bedan M, Grimm D, Wehland M, Simonsen U, Infanger M, Kruger M: A Focus on Macitentan in the Treatment of Pulmonary Arterial Hypertension. Basic Clin Pharmacol Toxicol. 2018 Aug;123(2):103-113. doi: 10.1111/bcpt.13033. Epub 2018 Jun 5. [Article]
- Sidharta PN, Treiber A, Dingemanse J: Clinical pharmacokinetics and pharmacodynamics of the endothelin receptor antagonist macitentan. Clin Pharmacokinet. 2015 May;54(5):457-71. doi: 10.1007/s40262-015-0255-5. [Article]
- FDA Approved Drug Products: OPSUMIT (macitentan) tablets [Link]
- DPD Approved Drug Products: Opsynvi (tadalafil/macitentan) combination tablets [Link]
- FDA Approved Drug Products: Opsynvi (macitentan and tadalafil) tablets for oral use [Link]
- External Links
- KEGG Drug
- D10135
- PubChem Compound
- 16004692
- PubChem Substance
- 175427162
- ChemSpider
- 13134960
- BindingDB
- 50395626
- 1442132
- ChEBI
- 76607
- ChEMBL
- CHEMBL2103873
- ZINC
- ZINC000043202140
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Macitentan
- FDA label
- Download (836 KB)
- MSDS
- Download (105 KB)
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample dataNot Available Completed Not Available Pulmonary Arterial Hypertension (PAH) 2 somestatus stop reason just information to hide 4 Completed Other Cardiac Allograft Vasculopathy 1 somestatus stop reason just information to hide 4 Completed Treatment Portopulmonary Hypertension 1 somestatus stop reason just information to hide 4 Completed Treatment Pulmonary Arterial Hypertension (PAH) 1 somestatus stop reason just information to hide 4 Terminated Treatment Pulmonary Arterial Hypertension (PAH) 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet Oral 10 mg Tablet, coated Oral 10 mg Tablet, film coated Oral 10 mg/1 Tablet, film coated Oral 10 MG Tablet, film coated Oral 10.00 mg Tablet Oral Tablet, film coated Oral Tablet Oral 10.000 mg - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US8268847 No 2012-09-18 2029-04-18 US US8367685 No 2013-02-05 2028-10-04 US US9265762 No 2016-02-23 2027-05-29 US US7094781 No 2006-08-22 2022-10-12 US US10946015 No 2021-03-16 2026-11-25 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 134-136°C MSDS - Predicted Properties
Property Value Source Water Solubility 0.00668 mg/mL ALOGPS logP 3.05 ALOGPS logP 3.69 Chemaxon logS -4.9 ALOGPS pKa (Strongest Acidic) 7.76 Chemaxon pKa (Strongest Basic) 3.26 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 9 Chemaxon Hydrogen Donor Count 2 Chemaxon Polar Surface Area 128.22 Å2 Chemaxon Rotatable Bond Count 9 Chemaxon Refractivity 126.98 m3·mol-1 Chemaxon Polarizability 50.55 Å3 Chemaxon Number of Rings 3 Chemaxon Bioavailability 1 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 204.09677 predictedDeepCCS 1.0 (2019) [M-H]- 204.09677 predictedDeepCCS 1.0 (2019) [M+H]+ 206.45477 predictedDeepCCS 1.0 (2019) [M+H]+ 206.45477 predictedDeepCCS 1.0 (2019) [M+Na]+ 213.27028 predictedDeepCCS 1.0 (2019) [M+Na]+ 213.27028 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Antagonist
- General Function
- Receptor for endothelin-1. Mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. The rank order of binding affinities for ET-A is: ET1 > ET2 >> ET3
- Specific Function
- endothelin receptor activity
- Gene Name
- EDNRA
- Uniprot ID
- P25101
- Uniprot Name
- Endothelin-1 receptor
- Molecular Weight
- 48721.76 Da
References
- Bolli MH, Boss C, Binkert C, Buchmann S, Bur D, Hess P, Iglarz M, Meyer S, Rein J, Rey M, Treiber A, Clozel M, Fischli W, Weller T: The discovery of N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-p ropylsulfamide (Macitentan), an orally active, potent dual endothelin receptor antagonist. J Med Chem. 2012 Sep 13;55(17):7849-61. doi: 10.1021/jm3009103. Epub 2012 Aug 16. [Article]
- Bedan M, Grimm D, Wehland M, Simonsen U, Infanger M, Kruger M: A Focus on Macitentan in the Treatment of Pulmonary Arterial Hypertension. Basic Clin Pharmacol Toxicol. 2018 Aug;123(2):103-113. doi: 10.1111/bcpt.13033. Epub 2018 Jun 5. [Article]
- Thenappan T, Ormiston ML, Ryan JJ, Archer SL: Pulmonary arterial hypertension: pathogenesis and clinical management. BMJ. 2018 Mar 14;360:j5492. doi: 10.1136/bmj.j5492. [Article]
- FDA Approved Drug Products: OPSUMIT (macitentan) tablets [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Antagonist
- General Function
- Non-specific receptor for endothelin 1, 2, and 3. Mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system
- Specific Function
- endothelin receptor activity
- Gene Name
- EDNRB
- Uniprot ID
- P24530
- Uniprot Name
- Endothelin receptor type B
- Molecular Weight
- 49643.255 Da
References
- Bolli MH, Boss C, Binkert C, Buchmann S, Bur D, Hess P, Iglarz M, Meyer S, Rein J, Rey M, Treiber A, Clozel M, Fischli W, Weller T: The discovery of N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-p ropylsulfamide (Macitentan), an orally active, potent dual endothelin receptor antagonist. J Med Chem. 2012 Sep 13;55(17):7849-61. doi: 10.1021/jm3009103. Epub 2012 Aug 16. [Article]
- Bedan M, Grimm D, Wehland M, Simonsen U, Infanger M, Kruger M: A Focus on Macitentan in the Treatment of Pulmonary Arterial Hypertension. Basic Clin Pharmacol Toxicol. 2018 Aug;123(2):103-113. doi: 10.1111/bcpt.13033. Epub 2018 Jun 5. [Article]
- Thenappan T, Ormiston ML, Ryan JJ, Archer SL: Pulmonary arterial hypertension: pathogenesis and clinical management. BMJ. 2018 Mar 14;360:j5492. doi: 10.1136/bmj.j5492. [Article]
- FDA Approved Drug Products: OPSUMIT (macitentan) tablets [Link]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:19965576, PubMed:20702771, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:21490593, PubMed:21576599, PubMed:2732228). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:12865317, PubMed:14559847). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:15373842, PubMed:15764715, PubMed:22773874, PubMed:2732228). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:15373842, PubMed:15764715, PubMed:2732228). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981)
- Specific Function
- 1,8-cineole 2-exo-monooxygenase activity
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- Bedan M, Grimm D, Wehland M, Simonsen U, Infanger M, Kruger M: A Focus on Macitentan in the Treatment of Pulmonary Arterial Hypertension. Basic Clin Pharmacol Toxicol. 2018 Aug;123(2):103-113. doi: 10.1111/bcpt.13033. Epub 2018 Jun 5. [Article]
- Sidharta PN, Treiber A, Dingemanse J: Clinical pharmacokinetics and pharmacodynamics of the endothelin receptor antagonist macitentan. Clin Pharmacokinet. 2015 May;54(5):457-71. doi: 10.1007/s40262-015-0255-5. [Article]
- FDA Approved Drug Products: OPSUMIT (macitentan) tablets [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of polyunsaturated fatty acids (PUFA) (PubMed:18577768, PubMed:19965576, PubMed:20972997). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:18577768, PubMed:19965576, PubMed:20972997). Catalyzes the hydroxylation of carbon-hydrogen bonds. Hydroxylates PUFA specifically at the omega-1 position (PubMed:18577768). Catalyzes the epoxidation of double bonds of PUFA (PubMed:19965576, PubMed:20972997). Also metabolizes plant monoterpenes such as limonene. Oxygenates (R)- and (S)-limonene to produce carveol and perillyl alcohol (PubMed:11950794). Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine. Hydroxylates fenbendazole at the 4' position (PubMed:23959307)
- Specific Function
- (R)-limonene 6-monooxygenase activity
- Gene Name
- CYP2C19
- Uniprot ID
- P33261
- Uniprot Name
- Cytochrome P450 2C19
- Molecular Weight
- 55944.565 Da
References
- Bedan M, Grimm D, Wehland M, Simonsen U, Infanger M, Kruger M: A Focus on Macitentan in the Treatment of Pulmonary Arterial Hypertension. Basic Clin Pharmacol Toxicol. 2018 Aug;123(2):103-113. doi: 10.1111/bcpt.13033. Epub 2018 Jun 5. [Article]
- Sidharta PN, Treiber A, Dingemanse J: Clinical pharmacokinetics and pharmacodynamics of the endothelin receptor antagonist macitentan. Clin Pharmacokinet. 2015 May;54(5):457-71. doi: 10.1007/s40262-015-0255-5. [Article]
- FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
- FDA Approved Drug Products: OPSUMIT (macitentan) tablets [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids and steroids (PubMed:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599, PubMed:7574697, PubMed:9435160, PubMed:9866708). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599, PubMed:7574697, PubMed:9435160, PubMed:9866708). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:15766564, PubMed:19965576, PubMed:7574697, PubMed:9866708). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Exhibits low catalytic activity for the formation of catechol estrogens from 17beta-estradiol (E2) and estrone (E1), namely 2-hydroxy E1 and E2 (PubMed:12865317). Catalyzes bisallylic hydroxylation and hydroxylation with double-bond migration of polyunsaturated fatty acids (PUFA) (PubMed:9435160, PubMed:9866708). Also metabolizes plant monoterpenes such as limonene. Oxygenates (R)- and (S)-limonene to produce carveol and perillyl alcohol (PubMed:11950794). Contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenytoin, tolbutamide and losartan (PubMed:25994031)
- Specific Function
- (R)-limonene 6-monooxygenase activity
- Gene Name
- CYP2C9
- Uniprot ID
- P11712
- Uniprot Name
- Cytochrome P450 2C9
- Molecular Weight
- 55627.365 Da
References
- Bedan M, Grimm D, Wehland M, Simonsen U, Infanger M, Kruger M: A Focus on Macitentan in the Treatment of Pulmonary Arterial Hypertension. Basic Clin Pharmacol Toxicol. 2018 Aug;123(2):103-113. doi: 10.1111/bcpt.13033. Epub 2018 Jun 5. [Article]
- Sidharta PN, Treiber A, Dingemanse J: Clinical pharmacokinetics and pharmacodynamics of the endothelin receptor antagonist macitentan. Clin Pharmacokinet. 2015 May;54(5):457-71. doi: 10.1007/s40262-015-0255-5. [Article]
- FDA Approved Drug Products: OPSUMIT (macitentan) tablets [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576, PubMed:7574697). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576, PubMed:7574697). Primarily catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) with a preference for the last double bond (PubMed:15766564, PubMed:19965576, PubMed:7574697). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes all trans-retinoic acid toward its 4-hydroxylated form (PubMed:11093772). Displays 16-alpha hydroxylase activity toward estrogen steroid hormones, 17beta-estradiol (E2) and estrone (E1) (PubMed:14559847). Plays a role in the oxidative metabolism of xenobiotics. It is the principal enzyme responsible for the metabolism of the anti-cancer drug paclitaxel (taxol) (PubMed:26427316)
- Specific Function
- arachidonic acid epoxygenase activity
- Gene Name
- CYP2C8
- Uniprot ID
- P10632
- Uniprot Name
- Cytochrome P450 2C8
- Molecular Weight
- 55824.275 Da
References
- Bedan M, Grimm D, Wehland M, Simonsen U, Infanger M, Kruger M: A Focus on Macitentan in the Treatment of Pulmonary Arterial Hypertension. Basic Clin Pharmacol Toxicol. 2018 Aug;123(2):103-113. doi: 10.1111/bcpt.13033. Epub 2018 Jun 5. [Article]
- Sidharta PN, Treiber A, Dingemanse J: Clinical pharmacokinetics and pharmacodynamics of the endothelin receptor antagonist macitentan. Clin Pharmacokinet. 2015 May;54(5):457-71. doi: 10.1007/s40262-015-0255-5. [Article]
- FDA Approved Drug Products: OPSUMIT (macitentan) tablets [Link]
Carriers
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Binder
- General Function
- Binds water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs (Probable). Its main function is the regulation of the colloidal osmotic pressure of blood (Probable). Major zinc transporter in plasma, typically binds about 80% of all plasma zinc (PubMed:19021548). Major calcium and magnesium transporter in plasma, binds approximately 45% of circulating calcium and magnesium in plasma (By similarity). Potentially has more than two calcium-binding sites and might additionally bind calcium in a non-specific manner (By similarity). The shared binding site between zinc and calcium at residue Asp-273 suggests a crosstalk between zinc and calcium transport in the blood (By similarity). The rank order of affinity is zinc > calcium > magnesium (By similarity). Binds to the bacterial siderophore enterobactin and inhibits enterobactin-mediated iron uptake of E.coli from ferric transferrin, and may thereby limit the utilization of iron and growth of enteric bacteria such as E.coli (PubMed:6234017). Does not prevent iron uptake by the bacterial siderophore aerobactin (PubMed:6234017)
- Specific Function
- antioxidant activity
- Gene Name
- ALB
- Uniprot ID
- P02768
- Uniprot Name
- Albumin
- Molecular Weight
- 69365.94 Da
References
- Sidharta PN, Treiber A, Dingemanse J: Clinical pharmacokinetics and pharmacodynamics of the endothelin receptor antagonist macitentan. Clin Pharmacokinet. 2015 May;54(5):457-71. doi: 10.1007/s40262-015-0255-5. [Article]
- Bedan M, Grimm D, Wehland M, Simonsen U, Infanger M, Kruger M: A Focus on Macitentan in the Treatment of Pulmonary Arterial Hypertension. Basic Clin Pharmacol Toxicol. 2018 Aug;123(2):103-113. doi: 10.1111/bcpt.13033. Epub 2018 Jun 5. [Article]
- FDA Approved Drug Products: OPSUMIT (macitentan) tablets [Link]
- Kind
- Protein group
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Binder
- General Function
- Functions as a transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in the body. Appears to function in modulating the activity of the immune system during the acute-phase reaction
- Specific Function
- Not Available
Components:
References
Drug created at December 29, 2013 18:30 / Updated at May 05, 2024 22:57