In vitro metabolism of α7 neuronal nicotinic receptor agonist AZD0328 and enzyme identification for its N-oxide metabolite

Xenobiotica. 2011 Mar;41(3):232-42. doi: 10.3109/00498254.2010.536855. Epub 2011 Jan 13.

Abstract

1. AZD0328 was pharmacologically characterized as a α7 neuronal nicotinic receptor agonist intended for treatment of Alzheimer's disease. In vitro AZD0328 cross species metabolite profile and enzyme identification for its N-oxide metabolite were evaluated in this study. 2. AZD0328 was very stable in the human hepatocyte incubation, whereas extensively metabolized in rat, dog and guinea pig hepatocyte incubations. The N-oxidation metabolite (M6) was the only metabolite detected in human hepatocyte incubations, and it also appeared to be the major in vitro metabolic pathway in a number of preclinical species. In addition, N-glucuronide metabolite of AZD0328 was observed in human liver microsomes. 3. Other metabolic pathways in the preclinical species include hydroxylation in azabicyclo octane or furopyridine part of the molecule. Pyridine N-methylation of AZD0328 (M2) was identified as a dog specific metabolite, not observed in human or other preclinical species. 4. Multiple enzymes including CYP2D6, CYP3A4/5, FMO1 and FMO3 catalyzed AZD0328 metabolism. The potential for AZD0328 to be inhibited clinically by co-administered drugs or genetic polymorphism is relative low.

MeSH terms

  • Animals
  • Cyclic N-Oxides / metabolism*
  • Cytochrome P-450 CYP2D6 / metabolism
  • Cytochrome P-450 CYP3A / metabolism
  • Cytosol / metabolism
  • Dogs
  • Female
  • Furans / metabolism*
  • Guinea Pigs
  • Hepatocytes / metabolism
  • Humans
  • Male
  • Nicotinic Agonists / metabolism*
  • Oxygenases / metabolism
  • Quinuclidines / metabolism*
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Cyclic N-Oxides
  • Furans
  • Nicotinic Agonists
  • Quinuclidines
  • spiro(1-azabicyclo(2.2.2)octane-3,2'(3H)-furo(2,3-b)pyridine)
  • Oxygenases
  • dimethylaniline monooxygenase (N-oxide forming)
  • Cytochrome P-450 CYP2D6
  • Cytochrome P-450 CYP3A