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

Current palliative pharmacotherapy of Alzheimer’s disease based on the cholinergic hypothesisled to the development of four cholinesterase inhibitors. These compounds can bring prolongationof the symptom-free period in some patients. This is the frst report directly comparing donepeziland rivastigmine plasma and brain levels in in-vivo study. Donepezil and rivastigmine wereapplied i.m. to rats; the dose was calculated from clinical recommendations. The samples wereanalysed on an Agilent 1260 Series LC with UV/VIS detector. An analytical column (WatersSpherisorb S5 W (250 mm × 4.6 i.d.; 5 μm particle size)) with guard column (Waters SpherisorbS5 W (30 mm × 4.6 mm i.d.)) was used. The mobile phase contained acetonitrile and 50 mMsodium dihydrogen phosphate (17:83; v/v); pH 3.1. The LLOQ in rat plasma was 0.5 ng/mL fordonepezil and 0.8 ng/mL for rivastigmine, and the LLOQ in rat brain was 1.0 ng/mL for donepeziland 1.1 ng/mL for rivastigmine. Both compounds showed ability to target the central nervoussystem, with brain concentrations exceeding those in plasma. Maximum brain concentration afteri.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 easilyexpressed by plasma/brain AUCtotal ratios: donepezil ratio in the brain was nine-times higher thanin plasma and rivastigmine ratio was less than two-times higher than in plasma.