Pharmacokinetic and Pharmacodynamic Properties of Cholinesterase Inhibitors Donepezil, Tacrine, and Galantamine in Aged and Young Lister Hooded Rats

Abstract

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 C max of galantamine and prolonged t 1/2 (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.

Pharmacological, toxicological and neuronal localization assessment of galantamine/chitosan complex nanoparticles in rats: future potential contribution in Alzheimer’s disease management

“…As reported by Goh et al (2011), administering GH orally in rats exhibited a high bioavailability (83 ± 13%) and 1.7:1 ± 0.2 brain/blood ratio 1 h after administration. However, GH is metabolized by hepatic cytochrome P450 enzymes, 460% of its metabolites are excreted via urine, and it has a short half-life (t 1/2 ) in rats ($1.9 h) (Mannens et al, 2002).…”

“…It has been reported by Goh et al (2011) that GH has a low-protein binding (about 18%) and a large volume of distribution (5.5 l/kg); which account for the accompanying cholinomimetic side effects due to its distribution to peripheral tissues such as nausea, vomiting, diarrhea, gastrointestinal cramping, and muscle weakness (Moffat et al, 2011). The significant weight loss and decreased food intake observed in the oral GH solution treated group reflect the potential side effects of administering GH orally which could be too intense in humans that the treatment should be discontinued (Hager et al, 2014).…”

Enduring effects of tacrine on cocaine-reinforced behavior: Analysis by conditioned-place preference, temporal separation from drug reward, and reinstatement

“…Based on this, and the absence of liver toxicity associated with various other inhibitors, tacrine-induced hepatotoxicity is believed to be mediated by immunologic mechanisms or mitochondrial injury that is unrelated to cholinesterase inhibition (Alfirevic et al, 2007). Because absorption of oral tacrine is about one-third of that following intravenous delivery (Goh et al, 2011), bioavailability of the dose chosen for our study is only slightly below that used by Ma et al (2003). We found no evidence of hepatic toxicity, which may have been mitigated by administering of tacrine as a slow infusion rather than bolus dosing.…”

Age-Related Decline in Brain and Hepatic Clearance of Amyloid-Beta is Rectified by the Cholinesterase Inhibitors Donepezil and Rivastigmine in Rats

“…In addition, this observed effect with donepezil and rivastigmine was more pronounced in aged compared to young rats, which could be attributed to pharmacokinetic changes with age that influenced plasma levels of the two drugs. 48 It has been reported that the blood and brain concentrations of ChEIs are higher in aged than young rats. 48 …”