title: Metabolism and disposition of varenicline, a selective alpha4beta2 acetylcholine receptor partial agonist, in vivo and in vitro.
abstract: 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.
authors.affiliation: Department of Pharmacokinetics, Dynamics, and Drug Metabolism, Pfizer Global Research and Development, Groton Laboratories, Groton, CT 06340, USA. r.scott.obach@pfizer.com
authors.forename: R Scott
authors.initials: RS
authors.lastname: Obach
authors.forename: Anne E
authors.initials: AE
authors.lastname: Reed-Hagen
authors.forename: Suzanne S
authors.initials: SS
authors.lastname: Krueger
authors.forename: Beth J
authors.initials: BJ
authors.lastname: Obach
authors.forename: Thomas N
authors.initials: TN
authors.lastname: O'Connell
authors.forename: Kathleen S
authors.initials: KS
authors.lastname: Zandi
authors.forename: Sandra
authors.initials: S
authors.lastname: Miller
authors.forename: Jotham W
authors.initials: JW
authors.lastname: Coe
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001552:Benzazepines / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000652:urine; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005243:Feces / Q000737:chemistry; D005260:Female; D020719:Glucuronides / Q000737:chemistry / Q000378:metabolism; D006207:Half-Life; D000882:Haplorhini; D006801:Humans; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D009005:Monosaccharides / Q000737:chemistry / Q000378:metabolism; D018722:Nicotinic Agonists / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D010429:Pentoses / Q000378:metabolism; D011810:Quinoxalines / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism; D013045:Species Specificity; D000068580:Varenicline
chemical_list: C507861:2-hydroxyvarenicline; D001552:Benzazepines; D002250:Carbon Radioisotopes; D020719:Glucuronides; D009005:Monosaccharides; C507864:N-formylvarenicline; C507865:N-glucosylvarenicline; D018722:Nicotinic Agonists; D010429:Pentoses; D011810:Quinoxalines; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; C507863:varenicline N-carbamoylglucuronide; D000068580:Varenicline