title: Brain levels and acetylcholinesterase inhibition with galantamine and donepezil in rats, mice, and rabbits.
abstract: Galantamine is a rather weak acetylcholinesterase (AChE) inhibitor, currently approved for the symptomatic treatment of Alzheimer's disease, with possible additional allosteric potentiating effects at the nicotinic ACh receptor (nAChR). Earlier data from in vitro biochemical tests suggest that donepezil is 40- to 500-fold more potent than galantamine in inhibiting AChE. In this study, both brain levels and Ki values for AChE inhibition for donepezil and galantamine in rat, mouse, and rabbit after subcutaneous application were determined. Clearance of galantamine from the brain is in general faster that donepezil and is faster in rabbits compared to rats and mice. The brain-to-plasma ratio for galantamine and donepezil, respectively, ranges from 1.2 to 1.5 in the rabbit, 3.3 to 5.2 in the mouse, and 6.6 to 13 in the rat. Galantamine doses between 1.5 and 5 mg/kg are appropriate to reach brain levels within the documented optimal allosteric potentiating ligand dose-response. Ki values of brain AChE inhibition for galantamine and donepezil, respectively, are 7.1 and 2.3 microg/g in rats, 8.3 and 0.65 microg/g for mice, and 19.1 and 1.3 microg/g in rabbits. The data also suggest that for a similar degree of brain AChE inhibition, 3-15 times higher galantamine than donepezil doses are needed.
authors.affiliation: In Silico Biosciences, Inc., 686 Westwind Drive, Berwyn, PA 19312, USA. Hugo-Geerts@In-Silico-Biosciences.com
authors.forename: Hugo
authors.initials: H
authors.lastname: Geerts
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Guillaumat
authors.forename: Christopher
authors.initials: C
authors.lastname: Grantham
authors.forename: Wilhelmina
authors.initials: W
authors.lastname: Bode
authors.forename: Katelijne
authors.initials: K
authors.lastname: Anciaux
authors.forename: Sohel
authors.initials: S
authors.lastname: Sachak
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D005702:Galantamine / Q000494:pharmacology*; D007189:Indans / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010880:Piperidines / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
chemical_list: D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D005702:Galantamine; D000077265:Donepezil; D000110:Acetylcholinesterase