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.