Metabolism, transport, and physiologically based pharmacokinetic modelling of novel tacrine derivatives

[摘要] Alzheimer’s disease (AD) is the most prevalent form of dementia affecting theelderly population, and its burden is rapidly growing both in Canada and worldwide. As aresult, there is a substantial need for more effective treatments. The first drug that wasapproved for the management of AD symptoms was tacrine, a dual cholinesteraseinhibitor. However, tacrine has since been discontinued after signs of hepatotoxicity wereobserved in a considerable proportion of patients. This toxicity has been linked to certainmetabolites of tacrine formed by oxidation via the hepatic enzyme CYP1A2. Despite thisissue, tacrine has remained a popular scaffold for the design of novel anti-Alzheimer’sagents. While tacrine is an example of the ;;one drug, one target” approach, a popularstrategy involves functionalizing tacrine into a multi-targeted compound to target severalpathways in the complex pathology of AD.In this regard, a library of tacrine derivatives was developed that exhibited bothpotent cholinesterase inhibition and the ability to inhibit the formation of thecharacteristic beta-amyloid plaques. Out of 25 starting compounds, nine compounds wereexamined further using in vitro and in silico techniques to investigate binding interactionswith CYP1A2 and CYP3A4 (to assess potential for hepatotoxicity) and P-gp (to predictcentral nervous system permeability). Three of the remaining nine compounds displayedthe desired properties and further experiments were conducted with these compounds todetermine metabolic clearance. These results were incorporated into a physiologicallybased pharmacokinetic model that was used to predict the dose needed to reach targetbrain concentrations in a preclinical study.

[发布机构] University of Waterloo

[效力级别] tacrine

[关键词] pharmacokinetics;tacrine;PBPK;Alzheimer"s disease;CYP450;P-glycoprotein;Pharmacy