Journal of Drug Metabolism & Toxicology
Open Access

Abstract

Pharmacokinetic and Pharmacodynamic Characteristics of Donepezil: From Animal Models to Human Applications

Akiko Kiriyama*

Alzheimer's disease is associated with a decline in Acetylcholine (ACh) levels, leading to cognitive impairment. Donepezil, Acetylcholinesterase (AChE) inhibitor, treats Alzheimer's disease by slowing ACh degradation, thus decelerating symptom progression. The pharmacokinetic characteristics of donepezil have been studied in experimental animals and humans, providing insights into its distribution, metabolism and excretion. Donepezil rapidly crosses the Blood-Brain Barrier (BBB) and is primarily metabolized in the liver, with metabolites showing minimal brain permeability. In rats, the maximum concentration of donepezil in the brain occurs two hours after administration, and the increase in ACh in the brain roughly coincides with plasma levels. Similar linear pharmacokinetics have also been observed in humans. However, species-specific differences in hepatic metabolism and plasma protein binding contribute to the variations in clearance between rats and humans. Once-daily dosing in clinical settings is supported by its long half-life (t1/2) of approximately 80 h. Cardiotoxicity has been observed when donepezil is co-administered with cilostazol, an antiplatelet agent that inhibits efflux transporters, leading to donepezil accumulation in the heart. Clinical studies indicate that although combination therapy improves cognitive function in patients with mild dementia, it may pose a risk of cardiovascular side effects. Pharmacokinetic/Pharmacodynamic (PK/PD) modeling has provided valuable insights into the relationship between plasma pharmacokinetics and AChE inhibition profiles, aiding the development of new dosage forms such as transdermal patches. These findings contribute to the understanding of the efficacy of donepezil and its potential drug interactions, providing more effective treatment strategies for Alzheimer's disease, especially in cases of polypharmacy.

Published Date: 2024-11-29; Received Date: 2024-10-28