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 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.
Footnotes
This work was supported by GlaxoSmithKline, R&D China.
This work contains part of C.W.G.'s thesis (Investigating the Influence of Age on Pharmacokinetic and Pharmacodynamic Characteristics of Gold Standard Alzheimer's Disease Drugs in the Lister-Hooded Rat) submitted to the National University of Singapore in 2009 in partial fulfillment of the requirements for the Master of Science (Pharmacology) degree.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.110.035964.
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ABBREVIATIONS:
- PK
- pharmacokinetic
- PD
- pharmacodynamic
- LH
- Lister hooded
- ChEI
- cholinesterase inhibitor
- AD
- Alzheimer's disease
- ACh
- acetylcholine
- ChE
- cholinesterase
- F344
- Fischer 344
- IS
- internal standard
- LC-MS/MS
- liquid chromatography with tandem mass spectrometric detection
- MRT
- mean residence time
- AUC
- area under concentration-time curve
- TIS
- TurboIonSpray
- AChE
- acetylcholinesterase
- BChE
- butyrylcholinesterase
- mAChR
- muscarinic acetylcholine receptor
- ANOVA
- analysis of variance.
- Received August 18, 2010.
- Accepted December 8, 2010.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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