Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Margarete-Höppel-Platz 1, 97080, Würzburg, Germany.
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, 60528, Frankfurt, Germany.
Int J Clin Pharm. 2023 Oct;45(5):1107-1117. doi: 10.1007/s11096-023-01588-8. Epub 2023 May 11.
Pharmacogenetics (PGx), especially in regard to CYP2D6, is gaining more importance in routine clinical settings. Including phenoconversion effects (PC) in result interpretation could maximize its potential benefits. However, studies on genetics of pharmacokinetic genes including the functional enzyme status are lacking.
The retrospective analyses of clinical routine data aimed to investigating how the CYP2D6 functional enzyme status affects serum concentrations and metabolite-to-parent ratios of seven common psychotropic drugs and allows an evaluation of the relevance of this information for patient care.
Two patient cohorts (total n = 316; 44.2 ± 15.4 years) were investigated for the CYP2D6 functional enzyme status and its associations with drug exposure and metabolism of venlafaxine, amitriptyline, mirtazapine, sertraline, escitalopram, risperidone and quetiapine.
We found an increase in intermediate and poor metabolizers, as well as a decrease in normal metabolizers of CYP2D6 when including PC. Moreover, we found associations between amitriptyline exposure with the phenoconversion-corrected activity score of CYP2D6 (Spearman correlation; p = 0.03), and risperidone exposure with CYP2D6 functional enzyme status (Kruskal-Wallis test; p = 0.01), as well as between metabolite-to-parent ratio of venlafaxine and risperidone with CYP2D6 functional enzyme status (Kruskal-Wallis test; p < 0.001; p = 0.05).
The data stress the relevance of PC-informed PGx in psychopharmacological treatment and suggest that PC should be included in PGx result interpretation when PGx is implemented in routine clinical care, especially before initiating amitriptyline- or risperidone-treatment, to start with a dose adequate to the respective CYP2D6 functional enzyme status. Moreover, PGx and therapeutic drug monitoring should be used complementary but not alternatively.
药物遗传学（PGx），特别是 CYP2D6，在常规临床环境中越来越重要。将表型转化效应（PC）纳入结果解释可以最大限度地发挥其潜在益处。然而，关于包括功能酶状态在内的药物代谢动力学基因的遗传研究还很缺乏。
本回顾性分析旨在研究 CYP2D6 功能酶状态如何影响七种常见精神药物的血清浓度和代谢物与母体的比值，并评估该信息对患者治疗的相关性。
对两个患者队列（共 316 例；年龄 44.2±15.4 岁）进行 CYP2D6 功能酶状态及其与文拉法辛、阿米替林、米氮平、舍曲林、艾司西酞普兰、利培酮和喹硫平暴露和代谢的相关性研究。
我们发现，在包括表型转化后，中间代谢型和弱代谢型患者增加，而正常代谢型患者减少。此外，我们发现，阿米替林暴露与 CYP2D6 表型转化校正后活性评分之间存在相关性（Spearman 相关分析；p=0.03），利培酮暴露与 CYP2D6 功能酶状态之间存在相关性（Kruskal-Wallis 检验；p=0.01），文拉法辛和利培酮的代谢物与母体比值与 CYP2D6 功能酶状态之间也存在相关性（Kruskal-Wallis 检验；p<0.001；p=0.05）。
这些数据强调了在精神药理学治疗中应用 PC 指导的 PGx 的相关性，并建议在常规临床护理中实施 PGx 时，应将 PC 纳入 PGx 结果解释，尤其是在开始阿米替林或利培酮治疗之前，应根据各自的 CYP2D6 功能酶状态给予适当的剂量。此外，PGx 和治疗药物监测应互补而不是替代使用。
