title: Pharmacokinetic and pharmacodynamic properties of cholinesterase inhibitors donepezil, tacrine, and galantamine in aged and young Lister hooded rats.
abstract: Physiological alterations that may change pharmacological response accompany aging. Pharmacokinetic/pharmacodynamic properties of cholinesterase inhibitors (ChEIs) used in the treatment of Alzheimer's disease, donepezil, tacrine, and galantamine, were investigated in an aged Lister hooded rat model. Intravenous and oral 6-h blood sampling profiles in old (30 months old) and young (7 months old) rats revealed pharmacokinetic changes similar to those in humans with an approximately 40% increase in C(max) of galantamine and prolonged t(1/2) (1.4-fold) and mean residence time (1.5-fold) of donepezil. Tacrine disposition was maintained with age, and area under the concentration-time curve and clearance in old rats were similar to those in young rats for all drugs tested as was bioavailability. Old rats showed a trend of increased pharmacodynamic sensitivity (<20%) to ChEIs in cholinesterase activity assays, which was attributed to pharmacokinetic effects because a trend of higher blood and brain concentrations was seen in the old rats although brain/blood ratios remained unaffected. Enhanced cholinergic-mediated behaviors such as tremor, hypothermia, salivation, and lacrimation were also observed in the old rats, which could not be accounted for by a similar magnitude of change in pharmacokinetics. A decrease in expression of muscarinic acetylcholine receptor subtype 2 detected in old rat brains was postulated to play a role. Greater age effects in both pharmacokinetics and pharmacodynamics of donepezil and tacrine were seen in previous studies with Fischer 344 rats, indicating a potential risk in overreliance on this rat strain for aging studies.
authors.affiliation: Neural Pathways Discovery Performance Unit (Research and Development China), Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Singapore. catgoh@live.com
authors.forename: Catherine W
authors.initials: CW
authors.lastname: Goh
authors.forename: Chiu Cheong
authors.initials: CC
authors.lastname: Aw
authors.forename: Jasinda H
authors.initials: JH
authors.lastname: Lee
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Chen
authors.forename: Edward R
authors.initials: ER
authors.lastname: Browne
mesh_terms: D000375:Aging; D000818:Animals; D001682:Biological Availability; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D002802:Cholinesterases / Q000097:blood / Q000378:metabolism; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D005702:Galantamine / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D006207:Half-Life; D007035:Hypothermia / Q000139:chemically induced; D007189:Indans / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D008657:Metabolic Clearance Rate; D010880:Piperidines / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D011919:Rats, Inbred Strains; D043585:Receptor, Muscarinic M2 / Q000378:metabolism; D012472:Salivation / Q000187:drug effects; D013619:Tacrine / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D013666:Tears / Q000187:drug effects / Q000378:metabolism; D014202:Tremor / Q000139:chemically induced
chemical_list: D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D043585:Receptor, Muscarinic M2; D005702:Galantamine; D013619:Tacrine; D000077265:Donepezil; D002802:Cholinesterases