Investigating the influence of Age on Pharmacokinetic and Pharmacodynamic characteristics of Gold standard Alzheimer's Disease drugs in the lister - Hooded Rat.

Abstract

Ageing accompanies physiological alterations that may change pharmacological response. PK/PD properties of AD drugs Aricept, Tacrine, Galantamine, and Memantine, were investigated in an aged Lister-hooded rat model. Intravenous and oral 6h blood-sampling profiles in old (30-months) and young (7-months) rats revealed similar PK changes to humans with significant increase in Cmax of Galantamine and prolonged half-life of Aricept. A trend of slightly decreased clearance was seen for all drugs, correlating with a reduction of CYP1A and 3A activity with age, although bioavailability remained unchanged. Brain:blood ratios of the drugs were maintained in old rats supported by unchanged brain P-glycoprotein mRNA expression. Old rats reported increased PD sensitivity to cholinesterase inhibitors (ChEIs) which was attributed to PK effects and decreased muscarinic acetylcholine receptor subtype 2 expression. Similar PK/PD studies of ChEIs with Fischer344 rats saw greater age effects, indicating a potential risk in over-reliance of a single strain for ageing studies.