细胞色素 P4502D6 功能多态性在阿尔茨海默病患者多奈哌齐疗效中的作用。

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

机构信息

Geriatric Unit & Gerontology-Geriatrics Research Laboratory, Department of Medical Sciences, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy.

出版信息

Pharmacogenet Genomics. 2011 Apr;21(4):225-30. doi: 10.1097/FPC.0b013e32833f984c.

DOI:10.1097/FPC.0b013e32833f984c

PMID:20859244

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.

摘要

目的

细胞色素 P450（CYP）2D6 酶主要负责代谢多奈哌齐，多奈哌齐是一种乙酰胆碱酯酶抑制剂，目前用于治疗轻度至中度阿尔茨海默病（AD）的症状。CYP2D6 基因中的功能多态性可能会影响酶活性，从而影响多奈哌齐的代谢。本研究旨在评估 CYP2D6 基因中的 16 种功能性多态性对轻度至中度 AD 患者多奈哌齐治疗临床反应的影响。

方法

在这项多中心前瞻性队列研究中，我们评估了 57 名无亲缘关系的高加索人，这些人根据美国国立神经病学和通信障碍及中风-阿尔茨海默病和相关障碍协会工作组的标准被临床诊断为 AD。患者接受多奈哌齐（5-10mg/天）治疗 6 个月。根据国家卫生与临床卓越研究所的要求，在 6 个月的随访时评估多奈哌齐治疗的反应。通过高通量基因分析对 16 种具有临床意义的 CYP2D6 基因变异进行鉴定。

结果

57 名患者中有 38 名（67%）是多奈哌齐治疗的应答者，19 名（33%）是无应答者。应答者中具有降低或缺乏酶活性的基因变异的频率明显高于无应答者（73.68%比 36.84%；P=0.005）。CYP2D6 酶活性降低或缺失的基因变异的存在与多奈哌齐治疗的临床反应显著相关（优势比=6.286；95%置信区间=1.828-21.667）。