Metabolism and disposition of varenicline, a selective alpha4beta2 acetylcholine receptor partial agonist, in vivo and in vitro. Export

@article{citeulike:1073098, 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.}, address = {Department of Pharmacokinetics, Dynamics, and Drug Metabolism, Pfizer Global Research and Development, Groton Laboratories, Groton, CT 06340, USA. r.scott.obach@pfizer.com}, author = {Obach, R. S. and Reed-Hagen, A. E. and Krueger, S. S. and Obach, B. J. and O'Connell, T. N. and Zandi, K. S. and Miller, S. and Coe, J. W.}, citeulike-article-id = {1073098}, citeulike-linkout-0 = {http://dx.doi.org/10.1124/dmd.105.006767}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/16221753}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=16221753}, doi = {10.1124/dmd.105.006767}, issn = {0090-9556}, journal = {Drug Metab Dispos}, keywords = {cholinergic, pharmacokinetic, substance\_abuse}, month = {January}, number = {1}, pages = {121--130}, posted-at = {2007-01-28 23:11:52}, priority = {0}, title = {Metabolism and disposition of varenicline, a selective alpha4beta2 acetylcholine receptor partial agonist, in vivo and in vitro.}, url = {http://dx.doi.org/10.1124/dmd.105.006767}, volume = {34}, year = {2006} }

TY - JOUR ID - citeulike:1073098 L3 - citeulike-article-id:1073098 N2 - 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. IS - 1 JF - Drug Metab Dispos SN - 0090-9556 AD - Department of Pharmacokinetics, Dynamics, and Drug Metabolism, Pfizer Global Research and Development, Groton Laboratories, Groton, CT 06340, USA. r.scott.obach@pfizer.com EP - 130 TI - Metabolism and disposition of varenicline, a selective alpha4beta2 acetylcholine receptor partial agonist, in vivo and in vitro. VL - 34 SP - 121 KW - cholinergic KW - pharmacokinetic KW - substance_abuse AU - Obach, RS AU - Reed-Hagen, AE AU - Krueger, SS AU - Obach, BJ AU - O'Connell, TN AU - Zandi, KS AU - Miller, S AU - Coe, JW PY - 2006/01// UR - http://dx.doi.org/10.1124/dmd.105.006767 ER -