Background: The efficacy of acetylcholinesterase inhibitors (AChE-I) might depend on blood concentration. While rivastigmine metabolism is independent of the cytochrome P450 system, its isoenzymes, especially CYP2D6, metabolize donepezil. CYP2D6 polymorphisms can cause altered enzyme activity resulting in lower or higher than expected drug concentrations of donepezil.
Objective: We investigated correlations between clinical efficacy and serum concentrations of rivastigmine and donepezil under special consideration of CYP 2D6 genotype or gene dose–dependent metabolism of donepezil.
Methods: Serum concentrations of donepezil and rivastigmine were measured by liquid chromatography – tandem mass spectrometry (LC-MS/MS). Real-time quantitative polymerase chain reaction (PCR) and allele-specific PCR were performed to assess CYP2D6 genotype and gene dose.
Results: Patients treated with rivastigmine (n=28) or donepezil (n=48) were included in the study. Both gene dose and metabolism type significantly predicted the level of donepezil serum concentration (p=0.019 and p=0.013, respectively). In the rivastigmine group, changes of the word list delayed recall subtest before treatment and under stable medication were significantly associated with rivastigmine serum levels (β=0.465; p=0.018). Drug serum concentrations were outside the recommended range in a substantial percentage of participants, which might have contributed to poor correlations between changes in cognitive measures and drug concentrations. Donepezil serum concentrations significantly depended on CYP2D6 gene dose.
Conclusion: Testing AChE-I serum concentration should be considered in patients without clinical response to treatment or those with severe side effects. Patients with donepezil drug levels outside the recommended range might additionally profit from CYP2D6 genotyping or treatment with an AChE-I independent of CYP metabolism.



中文翻译：

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考虑到多奈哌齐的 CYP2D6 基因型依赖性代谢对卡巴拉汀和多奈哌齐的治疗药物监测。

背景：乙酰胆碱酯酶抑制剂 (AChE-I) 的疗效可能取决于血药浓度。虽然卡巴拉汀代谢不依赖于细胞色素 P450 系统，但其同工酶，尤其是 CYP2D6，会代谢多奈哌齐。CYP2D6多态性可导致酶活性改变，导致多奈哌齐的药物浓度低于或高于预期。
目的：我们在特别考虑CYP 2D6基因型或多奈哌齐的基因剂量依赖性代谢的情况下，研究了卡巴拉汀和多奈哌齐的临床疗效与血清浓度之间的相关性。
方法：通过液相色谱-串联质谱 (LC-MS/MS) 测量多奈哌齐和卡巴拉汀的血清浓度。进行实时定量聚合酶链反应 (PCR) 和等位基因特异性 PCR 以评估CYP2D6基因型和基因剂量。
结果：接受卡巴拉汀（n=28）或多奈哌齐（n=48）治疗的患者被纳入研究。基因剂量和代谢类型均显着预测多奈哌齐血清浓度水平（分别为 p = 0.019 和 p = 0.013）。在卡巴拉汀组，治疗前和稳定用药期间单词表延迟回忆分测验的变化与卡巴拉汀血清水平显着相关（β=0.465；p=0.018）。在相当大比例的参与者中，药物血清浓度超出了推荐范围，这可能导致认知测量的变化与药物浓度之间的相关性较差。多奈哌齐血清浓度显着依赖于CYP2D6基因剂量。
结论：对治疗无临床反应或有严重副作用的患者应考虑检测 AChE-I 血清浓度。多奈哌齐药物水平超出推荐范围的患者可能额外受益于CYP2D6基因分型或独立于 CYP 代谢的 AChE-I 治疗。