title: In vitro metabolism of α7 neuronal nicotinic receptor agonist AZD0328 and enzyme identification for its N-oxide metabolite.
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.
authors.affiliation: Department of Clinical Pharmacology and DMPK, AstraZeneca Pharmaceuticals, Wilmington, DE, USA.
authors.forename: Diansong
authors.initials: D
authors.lastname: Zhou
authors.forename: Minli
authors.initials: M
authors.lastname: Zhang
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Ye
authors.forename: Chungang
authors.initials: C
authors.lastname: Gu
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Piser
authors.forename: Bernard A
authors.initials: BA
authors.lastname: Lanoue
authors.forename: Sara A
authors.initials: SA
authors.lastname: Schock
authors.forename: Yi-Fang
authors.initials: YF
authors.lastname: Cheng
authors.forename: Scott W
authors.initials: SW
authors.lastname: Grimm
mesh_terms: D000818:Animals; D003497:Cyclic N-Oxides / Q000378:metabolism*; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004285:Dogs; D005260:Female; D005663:Furans / Q000378:metabolism*; D006168:Guinea Pigs; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008297:Male; D018722:Nicotinic Agonists / Q000378:metabolism*; D010105:Oxygenases / Q000378:metabolism; D011812:Quinuclidines / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D003497:Cyclic N-Oxides; D005663:Furans; D018722:Nicotinic Agonists; D011812:Quinuclidines; C543642:spiro(1-azabicyclo(2.2.2)octane-3,2'(3H)-furo(2,3-b)pyridine); D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A