RT Journal Article SR Electronic T1 Metabolism, Pharmacokinetics, and Excretion of a Nonpeptidic Substance P Receptor Antagonist, Ezlopitant, in Normal Healthy Male Volunteers: Characterization of Polar Metabolites by Chemical Derivatization with Dansyl Chloride JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 1071 OP 1080 DO 10.1124/dmd.107.015362 VO 35 IS 7 A1 Chandra Prakash A1 John O'Donnell A1 S. Cyrus Khojasteh-Bakht YR 2007 UL http://dmd.aspetjournals.org/content/35/7/1071.abstract AB The excretion, biotransformation, and pharmacokinetics of ezlopitant [(2-benzhydryl-1-aza-bicyclo[2.2.2]oct-3-yl)-(5-isopropyl-2-methoxy-benzyl)-amine], a substance P receptor antagonist, were investigated in healthy male volunteers after oral administration of a single 200-mg (∼93 μCi/subject) dose of [14C]ezlopitant. The total recovery of administered radioactive dose was 82.8 ± 5.1, with 32.0 ± 4.2% in the urine and 50.8 ± 1.4% in the feces. Mean observed maximal serum concentrations for ezlopitant and total radioactivity were achieved at ∼2 h after oral administration; thus, ezlopitant was rapidly absorbed. Ezlopitant was extensively metabolized in humans, since no unchanged drug was detected in urine and feces. The major pathway of ezlopitant in humans was the result of the oxidation of the isopropyl side chain to form the ω-hydroxy and ω-1-hydroxy (M16) metabolites. M16 and ω,ω-1-dihydroxy (1,2-dihydroxy, M12) were identified as the major circulating metabolites accounting for 64.6 and 15.4% of total circulating radioactivity, respectively. In feces, the major metabolite M14 was characterized as the propionic acid metabolite and formed by further oxidation of the ω-hydroxy metabolite. The urinary metabolites were the result of cleaved metabolites caused by oxidative dealkylation of the 2-benzhydryl-1-aza-bicyclo[2.2.2]oct-3-yl moiety. The metabolites (M1A, M1B, and M4), approximately 34% of the total radioactivity in urine, were identified as benzyl amine derivatives. These were polar metabolites that were further characterized using the reaction with dansyl chloride to derivatize the primary amines and phenol moieties to less polar analytes. The other metabolites were the result of O-demethylation, dehydrogenation of the isopropyl group, and oxidation on the quinuclidine moiety. The American Society for Pharmacology and Experimental Therapeutics