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- Title
Impact of the CYP2D6 polymorphism on steady-state plasma concentrations and clinical outcome of donepezil in Alzheimer’s disease patients.
- Authors
Varsaldi, Federica; Miglio, Gianluca; Scordo, Maria Gabriella; Dahl, Marja-Liisa; Villa, Laura Maria; Biolcati, Aldo; Lombardi, Grazia
- Abstract
The aims of this study were to evaluate the impact of the CYP2D6 polymorphism on both the steady-state plasma concentrations (Cp) and the clinical outcome of donepezil, a selective acetylcholinesterase inhibitor used in the treatment of Alzheimer’s disease (AD). Forty-two patients of Caucasian ethnicity affected by probable AD were included in the study. All had been receiving therapy with donepezil for at least 3 months: 31 patients with 5 mg/day and 11 patients with 10 mg/day. The CYP2D6 genotype was analysed, and donepezil Cp was measured by using high-performance liquid chromatography. On the basis of their CYP2D6 genotype, 30 patients could be classified as homozygous extensive metabolizers (EM), 10 as heterozygous EM and 2 as ultrarapid metabolizers (UM). No poor metabolizer was found. The dose and body weight-corrected median donepezil Cp were slightly, though not significantly, lower in homozygous than in heterozygous EM (0.33 vs. 0.41 ng/ml/mg/kg, respectively). The latter group consistently showed a better clinical response to treatment, as measured by change in Mini-Mental State Examination score (median: 1.40 vs. −1.30, respectively). UM patients had lower Cp than EM patients and showed no clinical improvement. Our preliminary data suggest that the CYP2D6 polymorphism influences both donepezil metabolism and therapeutic outcome and that a knowledge of a patient’s CYP2D6 genotype together with donepezil concentration measurements might be useful in the context of improving the clinical efficacy of donepezil therapy.
- Subjects
GENETIC polymorphisms; ACETYLCHOLINESTERASE; ALZHEIMER'S disease; METABOLISM; CAUCASIAN race; PHARMACEUTICAL research
- Publication
European Journal of Clinical Pharmacology, 2006, Vol 62, Issue 9, p721
- ISSN
0031-6970
- Publication type
Article
- DOI
10.1007/s00228-006-0168-1