Role of cytochrome P4502D6 functional polymorphisms in the efficacy of donepezil in patients with Alzheimer's disease

Davide Seripa, Alessandra Bizzarro, Andrea Pilottof, Grazia D'Onofrio, Gennaro Vecchione, Antonietta P. Gallo, Leandro Cascavill, Francesco Paris, Elvira Grandone, Patrizia Mecoccie, Stefano A. Santinic, Carlo Masullo, Alberto Pilotto

Research output: Contribution to journalArticle

Abstract

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. Pharmacogenetics and Genomics 21:225-230

Original languageEnglish
Pages (from-to)225-230
Number of pages6
JournalPharmacogenetics and Genomics
Volume21
Issue number4
DOIs
Publication statusPublished - Apr 2011

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Cytochromes
Cytochrome P-450 CYP2D6
Alzheimer Disease
Genes
Enzymes
Therapeutics
National Institute of Neurological Disorders and Stroke
Communication Disorders
donepezil
Pharmacogenetics
Cholinesterase Inhibitors
National Institutes of Health (U.S.)
Genomics
Gene Frequency
Cytochrome P-450 Enzyme System
Cohort Studies
Odds Ratio
Genotype
Prospective Studies
Confidence Intervals

Keywords

  • Alzheimer's disease
  • Cytochrome P4502D6
  • Donepezil
  • Pharmacogenetics

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Molecular Medicine
  • Genetics(clinical)

Cite this

Role of cytochrome P4502D6 functional polymorphisms in the efficacy of donepezil in patients with Alzheimer's disease. / Seripa, Davide; Bizzarro, Alessandra; Pilottof, Andrea; D'Onofrio, Grazia; Vecchione, Gennaro; Gallo, Antonietta P.; Cascavill, Leandro; Paris, Francesco; Grandone, Elvira; Mecoccie, Patrizia; Santinic, Stefano A.; Masullo, Carlo; Pilotto, Alberto.

In: Pharmacogenetics and Genomics, Vol. 21, No. 4, 04.2011, p. 225-230.

Research output: Contribution to journalArticle

Seripa, Davide ; Bizzarro, Alessandra ; Pilottof, Andrea ; D'Onofrio, Grazia ; Vecchione, Gennaro ; Gallo, Antonietta P. ; Cascavill, Leandro ; Paris, Francesco ; Grandone, Elvira ; Mecoccie, Patrizia ; Santinic, Stefano A. ; Masullo, Carlo ; Pilotto, Alberto. / Role of cytochrome P4502D6 functional polymorphisms in the efficacy of donepezil in patients with Alzheimer's disease. In: Pharmacogenetics and Genomics. 2011 ; Vol. 21, No. 4. pp. 225-230.
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abstract = "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. Pharmacogenetics and Genomics 21:225-230",
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AU - Seripa, Davide

AU - Bizzarro, Alessandra

AU - Pilottof, Andrea

AU - D'Onofrio, Grazia

AU - Vecchione, Gennaro

AU - Gallo, Antonietta P.

AU - Cascavill, Leandro

AU - Paris, Francesco

AU - Grandone, Elvira

AU - Mecoccie, Patrizia

AU - Santinic, Stefano A.

AU - Masullo, Carlo

AU - Pilotto, Alberto

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N2 - 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. Pharmacogenetics and Genomics 21:225-230

AB - 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. Pharmacogenetics and Genomics 21:225-230

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