Impact of the CYP2D6 polymorphism on steady-state plasma concentrations and clinical outcome of donepezil in Alzheimer's disease patients.
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.
Varsaldi
Federica
F
DISCAFF Department, Amedeo Avogadro University of Eastern Piedmont, Via Bovio, 6, 28100 Novara, Italy.
Miglio
Gianluca
G
Scordo
Maria Gabriella
MG
Dahl
Marja-Liisa
ML
Villa
Laura Maria
LM
Biolcati
Aldo
A
Lombardi
Grazia
G
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
D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D000077265:Donepezil; D019389:Cytochrome P-450 CYP2D6