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.

Clinical Pharmacokinetics and Pharmacodynamics of Drugs in the Central Nervous System

“…However, in a study of donepezil in patients with Alzheimer’s, despite achieving concentrations in the CSF that were ten times lower than plasma, higher concentrations at 24 hours post-dose compared to 12 hours post-dose was observed in CSF but not plasma. (86,87) This is thought to be due to the degradation of P-gp protein in the progressive pathogenesis of Alzheimer’s (donepezil is a substrate of P-gp) that reduces the efflux of drug from CSF. (87) Given the localization of P-gp in BBB and its role in the efflux of drugs from the brain tissue, one might expect similar accumulation of donepezil to occur in brain tissue of Alzheimer’s patients as well, however, this is unknown.…”

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

“…Both compounds are able to target the CNS. Based on our results, the compounds may penetrate the blood–brain barrier via an active transport system such as in the case of donepezil . The brain concentration exceeds the plasmatic concentration relatively quickly, PC‐37 in the 15th minute and PC‐48 in the 30th minute after i.m.…”

“…Donepezil is a structurally different AChE inhibitor that was approved by the FDA in 1996 . Donepezil is a relatively low‐toxicity commonly used anti‐AD drug that has shown beneficial effects on cognitive function, daily living activities and some neuropsychiatric symptoms in AD patients . Donepezil may also play some role in mitigation of oxidative stress and in the improvement of cerebral blood flow .…”

The Concentration of Memantine in the Cerebrospinal Fluid of Alzheimer’s Disease Patients and Its Consequence to Oxidative Stress Biomarkers

“…2, 9, and 19 had ratios in the 0.00–25.54% range. Despite inter-individual differences, it is assumed that both the plasma and CSF levels of memantine are more stable among individual patients than are those of donepezil (Vališ et al, 2017).…”