Almorexant [(2R)-2-{(1S)-6, 7-dimethoxy-1-[2-(4-trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}-N-methyl-2-phenyl-acetamide], a tetrahydroisoquinoline derivative, is a dual orexin receptor antagonist with sleep-promoting properties in both animals and humans. This study investigated the disposition, metabolism, and elimination of almorexant in humans. After oral administration of a 200-mg dose of ¹⁴C-almorexant, almorexant was rapidly absorbed (Tmax = 0.8 hour), and the apparent terminal half-life (t(1/2)) was 17.8 hours. The radioactive dose was almost completely recovered with 78.0% of the administered radioactive dose found in feces and 13.5% in urine. Unchanged almorexant was not found in urine and represented 10% of the administered dose in feces. In total, 47 metabolites were identified of which 21 were shown to be present in plasma. There are four primary metabolites, the isomeric phenols M3 and M8, formed by demethylation, the aromatic isoquinolinium ion M5, formed by dehydrogenation, and M6, formed by oxidative dealkylation with loss of the phenylglycine moiety. Most of the subsequent products are formed by permutations of these primary metabolic reactions followed by conjugation of the intermediate phenols with glucuronic or sulfonic acid. The percentage of dose excreted in urine or feces for any of the metabolites did not exceed 10% of the administered radioactive dose, nor did any of the metabolites represent more than 10% of the total drug-related exposure. In conclusion, after rapid absorption, almorexant is extensively metabolized, and excretion of metabolites in feces is the predominant route of elimination in humans.