METABOLISM AND DISPOSITION OF VARENICLINE, A SELECTIVE α4β2 ACETYLCHOLINE RECEPTOR PARTIAL AGONIST, IN VIVO AND IN VITRO

• Published in: Drug metabolism and disposition Vol. 34; no. 1; p. 121
• Main Authors: R. Scott Obach, Anne E. Reed-Hagen, Suzanne S. Krueger, Beth J. Obach, Thomas N. O'Connell, Kathleen S. Zandi, Sandra Miller, Jotham W. Coe
• Format: Journal Article
• Language: English
• Published: American Society for Pharmacology and Experimental Therapeutics 01.01.2006
• ISSN: 0090-9556; 1521-009X
• DOI: 10.1124/dmd.105.006767

The metabolism and disposition of varenicline (7,8,9,10-tetrahydro-6,10-methano-6 H -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 [ 14 C]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 CO 2 atmosphere. The straightforward dispositional profile of varenicline should simplify its use in the clinic as an aid in smoking cessation.