PT - JOURNAL ARTICLE AU - Catherine W. Goh AU - Chiu Cheong Aw AU - Jasinda H. Lee AU - Christopher P. Chen AU - Edward R. Browne TI - Pharmacokinetic and Pharmacodynamic Properties of Cholinesterase Inhibitors Donepezil, Tacrine, and Galantamine in Aged and Young Lister Hooded Rats AID - 10.1124/dmd.110.035964 DP - 2011 Mar 01 TA - Drug Metabolism and Disposition PG - 402--411 VI - 39 IP - 3 4099 - http://dmd.aspetjournals.org/content/39/3/402.short 4100 - http://dmd.aspetjournals.org/content/39/3/402.full SO - Drug Metab Dispos2011 Mar 01; 39 AB - 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 Cmax of galantamine and prolonged t1/2 (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.