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

Document Type : Research article


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.


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 AUC
total 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

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


Main Subjects

  1. 1. Basiri A, Xiao M, McCarthy A, Dutta D, Byrareddy SN and Conda-Sheridan M. Design and synthesis of new piperidone grafted acetylcholinesterase inhibitors. Med. Chem. Lett. (2017) 27: 228-31.1.

    2. Davies P and Maloney AJF. Selective loss of central cholinergic neurons in Alzheimer disease. Lancet (1967) 2: 1403.

    1. Ballatore C, Lee VMY and Trojanowski JQ. Tau-Mediated Neurodegeneration in Alzheimer's disease and related disorders. Nat. Rev. Neurosci. (2007) 8: 663-72.
    2. Geldenhuys WJ and Darvesh AS. Pharmacotherapy of Alzheimer’s disease: current and future trends. Expert Rev. Neurother. (2015) 15: 3–5.
    3. Castellani RJ, Rolston RK and Smith MA. Alzheimer Disease. Dis. Mon. (2010) 56: 484-546.
    4. Sugimoto H, Yamanishi Y, Iimura Y and Kawakami Y. Donepezil hydrochloride (E2020) and other acetylcholinesterase inhibitors. Curr. Med. Chem. (2000) 7: 303-39.
    5. Valis M, Masopust J, Vysata O, Hort J, Dolezal R, Tomek J, Misik J, Kuca K and Karasova JZ. Concentration of donepezil in the cerebrospinal fluid of ad patients: evaluation of dosage sufficiency in standard treatment strategy. Neurotox. Res. (2017) 31: 162-8.
    6. Chen X, Magnotta VA, Duff K, Boles-Punto LL and Schultz SK. Donepezil effects on cerebral blood flow in older adults with mild cognitive deficits. J. Neuropsychiatry Clin. Neurosci. (2006) 18: 178–85.
    7. Tsukada H, Sato K, Kakiuchi T and Nishiyama S. Age-related impairment of coupling mechanism between neuronal activation and functional cerebral blood flow response was restored by cholinesterase inhibition: PET study with microdialysis in the awake monkey brain. Brain Res. (2000) 857: 158–64.
    8. Jann MW. Rivastigmine, a new-generation cholinesterase inhibitor for the treatment of Alzheimer's disease. Pharmacotherapy (2000) 20: 1-12.
    9. Greig NH, Utsuki T, Yu Q, Zhu X, Holloway HW, Perry T, Lee B, Ingram DK and Lahiri DK. A new therapeutic target in Alzheimer's disease treatment: Attention to butyrylcholinesterase. Curr. Med. Res. (2001) 17: 159-65.
    10. Ballard CG. Advances in the treatment of Alzheimer's disease: Benefits of dual cholinesterase inhibition. Eur. Neurol. (2002) 47: 64-70.
    11. Amini H and Ahmadiani A. High-performance liquid chromatographic determination of rivastigmine in human plasma for application in pharmacokinetic studies. Iran J. Pharm. Res. (2010) 9: 115-21.
    12. Karasova JZ, Hroch M, Musilek K and Kuca K. Small quaternary inhibitors K298 and K524: Cholinesterases inhibition, absorption, brain distribution, and toxicity. Neurotox. Res. (2016) 29: 267-74.
    13. Karasova JZ, Zemek F, Musilek K and Kuca K. Time-dependent changes of oxime K027 concentrations in different parts of rat central nervous system. Neurotox. Res. (2013) 23: 63-8.
    14. Giacobini E. Cholinesterase inhibitors: new role and therapeutic alternatives. Pharm. Res. (2004) 50: 433-40.
    15. Seltzer B. Donepezil: a review. Expert Opin. Drug Met. (2005) 1: 527–36.
    16. Tiseo PJ, Rogers SL and Friedhoff LT. Pharmacokinetic and pharmacodynamic profile of donepezil HCl following evening administration. Br. J. Clin. Pharmacol. (1998) 46 (Suppl 1): 13–8.
    17. Darreh-Shori T, Meurling L, Pettersson T, Hugosson K, Hellstrom-Lindahl E, Andreasen N, Minthon L and Nordberg A. Changes in the activity and protein levels of CSF acetylcholinesterases in relation to cognitive function of patients with mild Alzheimer’s disease following chronic donepezil treatment. J. Neural. Transm. (2006) 113: 1791–801.
    18. Jelic V and Darreh-Shori T. Donepezil: A review of pharmacological characteristics and role in the management of Alzheimer disease. Clin. Med. Insights Ther. (2010) 2: 771–88.
    19. Geerts H, Guillaumat PO, Grantham C, Bode W, Anciaux K and Sachak S. Brain levels and acetylcholinesterase inhibition with galantamine and donepezil in rats, mice, and rabbits. Brain Res. (2005) 1033: 186–93.
    20. Darreh-Shori T, Almkvist O, Guan ZZ, Garlind A, Strandberg B, Svensson AL, Soreq H, Hellstrom-Lindahl E and Nordberg A. Sustained cholinesterase inhibition in AD patients receiving rivastigmine for 12 months. Neurology (2002) 59: 563-72.
    21. Giacobini E, Spiegel R, Enz A, Veroff AE and Cutler NR. Inhibition of acetyl- and butyryl-cholinesterase in the cerebrospinal fluid of patients with Alzheimer's disease by rivastigmine: correlation with cognitive benefit. J. Neural. Transm. (2002) 109: 1053-65.
    22. Mzik M, Korabecny J, Nepovimova E, Vorisek V, Palicka V, Kuca K and Karasova JZ. An HPLC-MS method for the quantification of new acetylcholinesterase inhibitor PC-48 (7-MEOTA-donepezil like compound) in rat plasma: Application to a pharmacokinetic study. J. Chromatogr. B (2016) 1020: 85-9.
    23. Karasova JZ, Mzik M, Hroch M, Korabecny J, Nepovimova E, Vorisek V, Palicka V and Kuca K. The new acetylcholinesterase Inhibitors PC-37 and PC-48 (7-methoxytacrine-donepezil-like compounds): Characterization of their metabolites in human liver microsomes, pharmacokinetics and in-vivo formation of the major metabolites in rats. Bas. Clin. Pharm. Toxicol (2018) 122: 373-82.
    24. Karasova JZ, Sestak V, Korabecny J, Mezeiova E, Palicka V, Kuca K and Mzik M. 1-Benzyl-4-methylpiperidinyl moiety in donepezil: The priority ticket across the blood-brain-barrier in rats. J. Chromatogr. B (2018) 1092: 350-8.
    25. Sadowsky CH, Micca JL, Grossberg GT and Velting DM. Rivastigmine from capsules to patch: Therapeutic advances in the management of Alzheimer’s disease and Parkinson’s disease dementia. Prim. Care Companion CNS Disord. (2014) 16: 10.4088/PCC.14r01654.
    26. Klotz U. Pharmacokinetics and drug metabolism in the elderly. Drug Metab. Rev. (2009) 41: 67–76.
    27. Toornvliet R, van Berckel BN, Luurtsema G, Lubberink M, Geldof AA, Bosch TM, Oerlemans R, Lammertsma AA and Franssen EJ. Effect of age on functional P-glycoprotein in the blood-brain barrier measured by use of (R)-(11C)verapamil and positron emission tomography. Clin. Pharmacol. Ther. (2006) 79: 540–8.
    28. Bartels AL, Kortekaas R, Bart J, Willemsen AT, de Klerk OL, de Vries JJ, van Oostrom JC and Leenders KL. Blood-brain barrier P-glycoprotein function decreases in specific brain regions with aging: a possible role in progressive neurodegeneration. Neurobiol. Aging (2009) 30: 1818–24.
    29. Goh CW, Aw CC, Lee JH, Chen CP and Browne ER. Pharmacokinetic and pharmacodynamic properties of cholinesterase inhibitors donepezil, tacrine, and galantamine in aged and young lister hooded rats. Drug Metab. Dispos. (2011) 39: 402–11.