title: Absorption, distribution, metabolism, and excretion of macitentan, a dual endothelin receptor antagonist, in humans.
abstract: Macitentan is a tissue-targeting, dual endothelin receptor antagonist, currently under phase 3 investigation in pulmonary arterial hypertension. In this study the disposition and metabolism of macitentan were investigated following administration of a single oral 10 mg dose of (14)C-macitentan to six healthy male subjects. The total radioactivity in matrices was determined using liquid scintillation counting. The proposed structure of metabolites was based on mass spectrometry characteristics and, when available, confirmed by comparison with reference compounds. Mean (± SD) cumulative recovery of radioactivity from faeces and urine was 73.6% (± 6.2%) of the administered radioactive dose, with 49.7% (± 3.9%) cumulative recovery from urine, and 23.9% (± 4.8%) from faeces. In plasma, in addition to parent macitentan, ACT-132577, a pharmacologically active metabolite elicited by oxidative depropylation and the carboxylic acid metabolite ACT-373898 were identified. In urine, four entities were identified, with the hydrolysis product of ACT-373898 as the most abundant one. In faeces, five entities were identified, with the hydrolysis product of macitentan and ACT-132577 as the most abundant one. Concentrations of total radioactivity in whole blood were lower compared to plasma, which indicates that macitentan and its metabolites poorly bind to or penetrate into erythrocytes.
authors.affiliation: Clinical Pharmacology, Allschwil, Switzerland. Shirin.bruderer@actelion.com
authors.forename: Shirin
authors.initials: S
authors.lastname: Bruderer
authors.forename: Gérard
authors.initials: G
authors.lastname: Hopfgartner
authors.forename: Michael
authors.initials: M
authors.lastname: Seiberling
authors.forename: Janine
authors.initials: J
authors.lastname: Wank
authors.forename: Patricia N
authors.initials: PN
authors.lastname: Sidharta
authors.forename: Alexander
authors.initials: A
authors.lastname: Treiber
authors.forename: Jasper
authors.initials: J
authors.lastname: Dingemanse
mesh_terms: D002250:Carbon Radioisotopes / Q000378:metabolism; D002853:Chromatography, Liquid; D065128:Endothelin Receptor Antagonists; D005243:Feces / Q000737:chemistry; D006801:Humans; D008297:Male; D053858:Metabolic Networks and Pathways / Q000502:physiology*; D008875:Middle Aged; D015394:Molecular Structure; D011743:Pyrimidines / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000652:urine; D012588:Scintillation Counting; D013449:Sulfonamides / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000652:urine; D053719:Tandem Mass Spectrometry
chemical_list: D002250:Carbon Radioisotopes; D065128:Endothelin Receptor Antagonists; D011743:Pyrimidines; D013449:Sulfonamides; C572762:aprocitentan; C533860:macitentan