RT Journal Article SR Electronic T1 METABOLISM AND DISPOSITION OF VARENICLINE, A SELECTIVE α4β2 ACETYLCHOLINE RECEPTOR PARTIAL AGONIST, IN VIVO AND IN VITRO JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 121 OP 130 DO 10.1124/dmd.105.006767 VO 34 IS 1 A1 Obach, R. Scott A1 Reed-Hagen, Anne E. A1 Krueger, Suzanne S. A1 Obach, Beth J. A1 O'Connell, Thomas N. A1 Zandi, Kathleen S. A1 Miller, Sandra A1 Coe, Jotham W. YR 2006 UL http://dmd.aspetjournals.org/content/34/1/121.abstract AB The metabolism and disposition of varenicline (7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine), a partial agonist of the nicotinic acetylcholine receptor for the treatment of tobacco addiction, was examined in rats, mice, monkeys, and humans after oral administration of [14C]varenicline. In the circulation of all species, the majority of drug-related material was composed of unchanged varenicline. In all four species, drug-related material was primarily excreted in the urine. A large percentage was excreted as unchanged parent drug (90, 84, 75, and 81% of the dose in mouse, rat, monkey, and human, respectively). Metabolites observed in excreta arose via N-carbamoyl glucuronidation and oxidation. These metabolites were also observed in the circulation, in addition to metabolites that arose via N-formylation and formation of a novel hexose conjugate. Experiments were conducted using in vitro systems to gain an understanding of the enzymes involved in the formation of the N-carbamoylglucuronide metabolite in humans. N-Carbamoyl glucuronidation was catalyzed by UGT2B7 in human liver microsomes when incubations were conducted under a CO2 atmosphere. The straightforward dispositional profile of varenicline should simplify its use in the clinic as an aid in smoking cessation. The American Society for Pharmacology and Experimental Therapeutics