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METABOLISM AND DISPOSITION OF VARENICLINE, A SELECTIVE 4ß2 ACETYLCHOLINE RECEPTOR PARTIAL AGONIST, IN VIVO AND IN VITRO

Department of Pharmacokinetics, Dynamics, and Drug Metabolism (R.S.O., A.E.R., S.S.K., B.J.O.), NMR and Structural Chemistry Group (T.N.O.), Radiochemical Synthesis Group (K.S.Z., S.M.), and Medicinal Chemistry (J.W.C.), Pfizer Global Research and Development, Groton Laboratories, Groton, Connecticut

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.

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