Donepezil and Rivastigmine: Pharmacokinetic Profile and Brain-targeting After Intramuscular Administration in Rats

Zdarova Karasova, Jana; Hrabinova, Martina; Krejciova, Marketa; Jun, Daniel; Kuca, Kamil

doi:10.22037/ijpr.2019.1100723

Donepezil and Rivastigmine: Pharmacokinetic Profile and Brain-targeting After Intramuscular Administration in Rats

Document Type: Research article

Authors

¹ Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Hradec Kralove, Czech Republic.

² Biomedical Research Centre, University Hospital, Hradec Kralove, Czech Republic.

³ Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Hradec Kralove, Czech Republic

⁴ Biomedical Research Centre, University Hospital, Hradec Kralove, Czech Republic

⁵ Department of Chemistry, Faculty of Science, University of Hradec Kralove, Hradec Kralove, Czech Republic.

10.22037/ijpr.2019.1100723

Abstract

Current palliative pharmacotherapy of Alzheimer’s disease based on the cholinergic hypothesis
led to the development of four cholinesterase inhibitors. These compounds can bring prolongation
of the symptom-free period in some patients. This is the frst report directly comparing donepezil
and rivastigmine plasma and brain levels in in-vivo study. Donepezil and rivastigmine were
applied i.m. to rats; the dose was calculated from clinical recommendations. The samples were
analysed on an Agilent 1260 Series LC with UV/VIS detector. An analytical column (Waters
Spherisorb S5 W (250 mm × 4.6 i.d.; 5 μm particle size)) with guard column (Waters Spherisorb
S5 W (30 mm × 4.6 mm i.d.)) was used. The mobile phase contained acetonitrile and 50 mM
sodium dihydrogen phosphate (17:83; v/v); pH 3.1. The LLOQ in rat plasma was 0.5 ng/mL for
donepezil and 0.8 ng/mL for rivastigmine, and the LLOQ in rat brain was 1.0 ng/mL for donepezil
and 1.1 ng/mL for rivastigmine. Both compounds showed ability to target the central nervous
system, with brain concentrations exceeding those in plasma. Maximum brain concentration after
i.m. administration was reached in the 36 (8.34 ± 0.34 ng/mL) and 17 minute (6.18 ± 0.40 ng/mL),
respectively for donepezil and rivastigmine. The differences in brain profle can be most easily
expressed by plasma/brain AUCtotal ratios: donepezil ratio in the brain was nine-times higher than
in plasma and rivastigmine ratio was less than two-times higher than in plasma.

Graphical Abstract