Casopitant [1-piperidinecarboxamide,4-(4-acetyl-1-piperazinyl)-N-((1R)-1-(3,5-bis(trifluoromethyl)phenyl)-ethyl)-2-(4-fluoro-2-methylphenyl)-N-methyl-(2R,4S)] is a potent and selective antagonist of the neurokinin-1 (NK1) receptor, developed for the prevention of chemotherapy-induced nausea and vomiting and postoperative nausea and vomiting. Absorption, distribution, metabolism, and elimination of [(14)C]casopitant have been investigated in the mouse, rat, and dog after single oral administration and compared with those in humans. [(14)C]Casopitant was rapidly absorbed in all three species: the maximum plasma concentration of radioactivity was generally observed 0.5 to 2 h after a single oral dose. In dog and female rat, as observed for humans, the principal circulating radiolabeled components were unchanged casopitant and its hydroxylated derivative M13. In rats, there was an evident sex-related difference in the rate of elimination of drug-related material with elimination being more rapid in males than in females. In dogs and mice, no notable sex differences were observed in the pattern of excretion. The elimination of drug-related radioactivity was largely by metabolism, with metabolites excreted primarily in the feces. The predominant route of metabolism was the oxidation of the parent molecule, observed together with loss of the N-acetyl group, N-demethylation, and modification of piperazine with consequent opening and cleavage of the ring, giving a complex pattern of metabolites. Conjugation of some of those oxidized products with glucuronic acid was observed. Urinary excretion in all three species was a minor route of elimination, accounting for between 2 and 7% of the dose, with unchanged parent drug never quantifiable.