RT Journal Article SR Electronic T1 Disposition and Metabolism of [14C]SB-649868, an Orexin 1 and 2 Receptor Antagonist, in Humans JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 215 OP 227 DO 10.1124/dmd.110.035386 VO 39 IS 2 A1 Cecilia Renzulli A1 Mike Nash A1 Mark Wright A1 Steven Thomas A1 Stefano Zamuner A1 Mario Pellegatti A1 Paolo Bettica A1 Gary Boyle YR 2011 UL http://dmd.aspetjournals.org/content/39/2/215.abstract AB N-[[(2S)-1-[[5-(4-fluorophenyl)-2-methyl-4-thiazolyl]carbonyl]-2-piperidinyl]methyl]-4-benzofurancarboxamide (SB-649868) is a novel orexin 1 and 2 receptor antagonist under development for insomnia treatment. The disposition of [14C]SB-649868 was determined in eight healthy male subjects using an open-label study design after a single oral dose of 30 mg. Blood, urine, and feces were collected at frequent intervals after dosing, and samples were analyzed by high-performance liquid chromatography-mass spectrometry coupled with off-line radiodetection for metabolite profiling and characterization. NMR spectroscopy was also used to further characterize certain metabolites. Elimination of drug-related material was almost complete over a 9-day period, occurring principally via the feces (79%), whereas urinary excretion accounted only for 12% of total radioactivity. Mean apparent half-life (t1/2) of plasma radioactivity was notably longer (39.3 h), with respect to that of unchanged SB-649868 (4.8 h), suggesting the presence of more slowly cleared metabolites. SB-649868 and an unusual hemiaminal metabolite, M98 (2-[((2S)-1-{[5-(4-fluorophenyl)-2-methyl-1,3-thiazol-4-yl]carbonyl}-2-piperidinyl)methyl]-3,5-dihydroxy-3,4-dihydro-1(2H)-isoquinolinone; GSK2329163), resulting from oxidation of the benzofuran ring and subsequent rearrangement, were the principal circulating components in plasma extracts. Two additional minor metabolites were also observed: a benzofuran ring-opened carboxylic acid M25 ([2-({[((2S)-1-{[5-(4-fluorophenyl)-2-methyl-1,3-thiazol-4-yl]carbonyl}-2-piperidinyl)methyl]amino}carbonyl)-6-hydroxyphenyl]acetic acid; GSK2329158) and an amine metabolite (M8). SB-649868 was extensively metabolized, and only negligible amounts were excreted unchanged. The principal route of metabolism was via oxidation of the benzofuran ring with the resultant M25 being the principal metabolite in excreta, representing at least 12% of the administered dose across urine and feces.