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Received for publication August 3, 2005.
Revised October 7, 2005.
Accepted for publication October 7, 2005.
4
2 ACETYLCHOLINE RECEPTOR PARTIAL AGONIST, IN VIVO AND IN VITROThe metabolism and disposition of varenicline, 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 circulation of all species, the vast majority of drug-related material was comprised of unchanged varenicline. In all four species, drug-related material was primarily excreted in the urine, with a large percentage as unchanged parent drug (90, 84, 75, and 81% of 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 in order 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.
Key words:
glucuronidation, metabolite identification, pharmacokinetics
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