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

Drug Metab Dispos. 2006 Jan;34(1):121-30. doi: 10.1124/dmd.105.006767. Epub 2005 Oct 12.

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.

Publication types

  • Comparative Study

MeSH terms

  • Administration, Oral
  • Animals
  • Area Under Curve
  • Benzazepines / chemistry
  • Benzazepines / metabolism*
  • Benzazepines / pharmacokinetics*
  • Benzazepines / urine
  • Carbon Radioisotopes
  • Chromatography, High Pressure Liquid / methods
  • Drug Evaluation, Preclinical / methods
  • Feces / chemistry
  • Female
  • Glucuronides / chemistry
  • Glucuronides / metabolism
  • Half-Life
  • Haplorhini
  • Humans
  • Male
  • Mass Spectrometry / methods
  • Mice
  • Monosaccharides / chemistry
  • Monosaccharides / metabolism
  • Nicotinic Agonists / chemistry
  • Nicotinic Agonists / metabolism
  • Nicotinic Agonists / pharmacokinetics
  • Pentoses / metabolism
  • Quinoxalines / chemistry
  • Quinoxalines / metabolism*
  • Quinoxalines / pharmacokinetics*
  • Quinoxalines / urine
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Nicotinic / metabolism
  • Species Specificity
  • Varenicline

Substances

  • 2-hydroxyvarenicline
  • Benzazepines
  • Carbon Radioisotopes
  • Glucuronides
  • Monosaccharides
  • N-formylvarenicline
  • N-glucosylvarenicline
  • Nicotinic Agonists
  • Pentoses
  • Quinoxalines
  • Receptors, Nicotinic
  • nicotinic receptor alpha4beta2
  • varenicline N-carbamoylglucuronide
  • Varenicline