title: Concentration of Donepezil in the Cerebrospinal Fluid of AD Patients: Evaluation of Dosage Sufficiency in Standard Treatment Strategy.
abstract: Although some studies have described the pharmacokinetics and pharmacodynamics of donepezil in the peripheral compartment, studies focused on drug transport across the blood-brain barrier are still very rare. To our knowledge, the fluctuation in the cerebrospinal fluid concentration of donepezil after administration of the drug has not been described in the literature so far. We recruited 16 patients regularly taking a standard therapeutic dose of donepezil (10 mg per day). All patients (Caucasian race) were treated for at least three months with a stable dose of 10 mg per day prior to sample collection. Patients were divided into two groups depending on the time of plasma and cerebrospinal fluid sampling: 12 h (n = 9; 4 M/5F aged 78.68 ± 7.35 years) and 24 h (n = 7; 3 M/4F aged 77.14 ± 5.87 years) after donepezil administration. The cerebrospinal fluid sample was collected by standard lumbar puncture technique using a single-use traumatic needle. The samples were analysed on an Agilent 1260 Series liquid chromatograph comprising a degasser, a quaternary pump, a light-tight autosampler unit set, a thermostated column compartment, and a UV/VIS detector. Agilent ChemStation software, the statistical software Prism4, version 5.0 (GraphPad Software, USA), and IBM®SPSS®Statistics were used for the analysis of the results. The difference in plasma concentration of donepezil after 12 h (mean ± SEM; 39.99 ± 5.90 ng/ml) and after 24 h (29.38 ± 1.71 ng/ml) was nonsignificant. In contrast, the donepezil concentration in the cerebrospinal fluid was significantly higher in the 24-h interval (7.54 ± 0.55 ng/ml) compared with the 12-h interval (5.19 ± 0.83 ng/ml, which is ~70 % based on mean cerebrospinal fluid values). Based on these data, it is plausible to predict that donepezil might produce a stronger AChE inhibition in the brain at 24 h compared with 12 h following the administration. This information may help physicians individually adjust the time of drug administration in the patients according to time course of the disease symptoms.
authors.affiliation: Department of Neurology, Faculty of Medicine and University Hospital Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Valis
authors.affiliation: Department of Neurology, Faculty of Medicine and University Hospital Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic.|Department of Psychiatry, Faculty of Medicine and University Hospital Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic.
authors.forename: Jiri
authors.initials: J
authors.lastname: Masopust
authors.affiliation: Department of Neurology, Faculty of Medicine and University Hospital Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic.
authors.forename: Oldrich
authors.initials: O
authors.lastname: Vysata
authors.affiliation: Department of Neurology, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague, Czech Republic.|International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czech Republic.
authors.forename: Jakub
authors.initials: J
authors.lastname: Hort
authors.affiliation: Biomedical Research Center, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic.
authors.forename: Rafael
authors.initials: R
authors.lastname: Dolezal
authors.affiliation: Department of Neurology, Faculty of Medicine and University Hospital Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic.
authors.forename: Jiri
authors.initials: J
authors.lastname: Tomek
authors.affiliation: Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defense in Brno, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Misik
authors.affiliation: Biomedical Research Center, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic.
authors.forename: Kamil
authors.initials: K
authors.lastname: Kuca
authors.affiliation: Biomedical Research Center, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic. zdarova.jana@gmail.com.|Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defense in Brno, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic. zdarova.jana@gmail.com.
authors.forename: Jana Zdarova
authors.initials: JZ
authors.lastname: Karasova
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000188:drug therapy*; D001812:Blood-Brain Barrier; D002199:Capillary Permeability; D002800:Cholinesterase Inhibitors / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics / Q000627:therapeutic use; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007189:Indans / Q000097:blood / Q000134:cerebrospinal fluid* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D018697:Nootropic Agents / Q000097:blood / Q000134:cerebrospinal fluid* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010880:Piperidines / Q000097:blood / Q000134:cerebrospinal fluid* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013129:Spinal Puncture; D013997:Time Factors
chemical_list: D002800:Cholinesterase Inhibitors; D007189:Indans; D018697:Nootropic Agents; D010880:Piperidines; D000077265:Donepezil
keywords: Alzheimer’s disease; Cerebrospinal fluid concentrations; Clinical study; Donepezil