Role of cytochrome P4502D6 functional polymorphisms in the efficacy of donepezil in patients with Alzheimer's disease.
OBJECTIVE
Cytochrome P450 (CYP) 2D6 enzyme is the major responsible for the metabolism of donepezil, an inhibitor of acetyl cholinesterase currently used for the symptomatic treatment of mild-to-moderate Alzheimer's disease (AD). Functional polymorphisms in the CYP2D6 gene may affect enzyme activity and thus, the metabolism of donepezil. The aim of this study was to evaluate the effect of 16 functional polymorphisms in the CYP2D6 gene on the clinical response to donepezil treatment in patients with mild-to-moderate AD.


METHODS
In this multicenter prospective cohort study we evaluated 57 unrelated Caucasians clinically diagnosed as AD according to the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association Work Group criteria. Patients were treated with donepezil (5-10 mg/daily) for 6 months. The response to donepezil treatment was evaluated at 6-month follow-up according to the National Institute for Health and Clinical Excellence requirements. The identification of 16 clinically relevant CYP2D6 gene variants was performed by a high-throughput genetic analysis.


RESULTS
Thirty-eight of 57 patients (67%) were responders and 19 patients (33%) were nonresponders to donepezil treatment. A significantly higher frequency of gene variants conferring decreased or absent enzyme activity was observed in responder than in nonresponder patients (73.68% vs. 36.84%; P=0.005). The presence of gene variants conferring decreased or absent activity of the CYP2D6 enzyme was significantly associated with a clinical response to donepezil treatment (odds ratio=6.286; 95% confidence interval=1.828-21.667).


CONCLUSIONS
Functional polymorphisms in the CYP2D6 gene can influence the clinical efficacy of donepezil. The analysis of CYP2D6 genotypes may be useful in identifying subgroups of AD patients with different clinical response to donepezil treatment.
Seripa
Davide
D
Geriatric Unit & Gerontology-Geriatrics Research Laboratory, Department of Medical Sciences, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy. dseripa@operapadrepio.it
Bizzarro
Alessandra
A
Pilotto
Andrea
A
D'onofrio
Grazia
G
Vecchione
Gennaro
G
Gallo
Antonietta P
AP
Cascavilla
Leandro
L
Paris
Francesco
F
Grandone
Elvira
E
Mecocci
Patrizia
P
Santini
Stefano A
SA
Masullo
Carlo
C
Pilotto
Alberto
A
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics; D015331:Cohort Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D000077265:Donepezil; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007189:Indans / Q000627:therapeutic use*; D008297:Male; D018697:Nootropic Agents / Q000627:therapeutic use*; D010880:Piperidines / Q000627:therapeutic use*; D011110:Polymorphism, Genetic / Q000235:genetics*
D007189:Indans; D018697:Nootropic Agents; D010880:Piperidines; D000077265:Donepezil; D019389:Cytochrome P-450 CYP2D6