Impact of the CYP2D6 polymorphism on steady-state plasma concentrations and clinical outcome of donepezil in Alzheimer's disease patients

Eur J Clin Pharmacol. 2006 Sep;62(9):721-6. doi: 10.1007/s00228-006-0168-1. Epub 2006 Jul 15.


Objective: 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).

Methods: 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.

Results: 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.

Conclusions: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / blood
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / genetics
  • Alzheimer Disease / psychology
  • Cholinesterase Inhibitors / therapeutic use*
  • Cytochrome P-450 CYP2D6 / genetics*
  • Donepezil
  • Female
  • Genotype
  • Humans
  • Indans / blood
  • Indans / therapeutic use*
  • Male
  • Middle Aged
  • Piperidines / blood
  • Piperidines / therapeutic use*
  • Polymorphism, Genetic


  • Cholinesterase Inhibitors
  • Indans
  • Piperidines
  • Donepezil
  • Cytochrome P-450 CYP2D6