title: Impact of the CYP2D6 polymorphism on steady-state plasma concentrations and clinical outcome of donepezil in Alzheimer's disease patients.
abstract: 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.
authors.affiliation: DISCAFF Department, Amedeo Avogadro University of Eastern Piedmont, Via Bovio, 6, 28100 Novara, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Varsaldi
authors.forename: Gianluca
authors.initials: G
authors.lastname: Miglio
authors.forename: Maria Gabriella
authors.initials: MG
authors.lastname: Scordo
authors.forename: Marja-Liisa
authors.initials: ML
authors.lastname: Dahl
authors.forename: Laura Maria
authors.initials: LM
authors.lastname: Villa
authors.forename: Aldo
authors.initials: A
authors.lastname: Biolcati
authors.forename: Grazia
authors.initials: G
authors.lastname: Lombardi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000523:psychology; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D000077265:Donepezil; D005260:Female; D005838:Genotype; D006801:Humans; D007189:Indans / Q000097:blood / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000097:blood / Q000627:therapeutic use*; D011110:Polymorphism, Genetic
chemical_list: D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D000077265:Donepezil; D019389:Cytochrome P-450 CYP2D6