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首页> 外文期刊>Drug Design, Development and Therapy >Therapeutic Drug Monitoring of Rivastigmine and Donepezil Under Consideration of CYP2D6 Genotype-Dependent Metabolism of Donepezil
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Therapeutic Drug Monitoring of Rivastigmine and Donepezil Under Consideration of CYP2D6 Genotype-Dependent Metabolism of Donepezil

机译：考虑到Deinpezil的CYP2D6基因型依赖性代谢的Rivastigmine和Denpezil的治疗药物监测

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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.
机译：背景：乙酰胆碱酯酶抑制剂（ACHE-1）的功效可能取决于血液浓度。虽然Rivastigmine新陈代谢独立于细胞色素P450系统，但其同工酶，特别是CYP2D6，代谢Denpezil。 CYP2D6多态性可引起改变的酶活性，导致较低或高于多奈哌齐的预期药物浓度。目的：在特殊考虑CYP 2D6基因型或基因依赖于多种依赖性的特殊考虑下，研究了临床疗效和血清浓度与多奈哌齐的相关性。方法：通过液相色谱 - 串联质谱（LC-MS / MS）测量血清培养基浓度和脊酮的血清浓度。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：在研究中含有菌敏翅膀（n = 28）或多奈哌齐（n = 48）治疗的患者。两种基因剂量和代谢类型都显着预测了多奈哌妥血清浓度的水平（P = 0.019和P = 0.013）。在RIVASTIGMINE组中，在治疗和稳定药物下延迟召回子测试的单词列表延迟的变化与RIVASTIGMIN血清水平显着相关（β= 0.465; P = 0.018）。药物血清浓度在推荐范围之外，以大量的参与者百分比，这可能导致认知措施和药物浓度之间的变化之间的相关性差。 Denpezil血清浓度显着依赖于CYP2D6基因剂量。结论：在没有临床反应的患者中考虑疼痛-I血清浓度，没有临床反应或具有严重副作用的患者。在推荐范围之外的多奈哌齐药物水平的患者可以另外从CYP2D6基因分型或用ACHE-I依赖于CYP代谢来利润。

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