Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway.
Department of Life Sciences and Health, Oslo Metropolitan University, Oslo, Norway.
Basic Clin Pharmacol Toxicol. 2024 Jan;134(1):186-192. doi: 10.1111/bcpt.13954. Epub 2023 Oct 30.
Duloxetine is metabolized by cytochrome P450 (CYP)1A2 and CYP2D6. The aim of this study was to investigate the effect of the CYP2D6 genotype on duloxetine serum concentration adjusting for age and sex. Patients were included retrospectively from a therapeutic drug monitoring service. Multiple linear regression analysis was used to investigate the effect of CYP2D6 genotype, age and sex on the duloxetine concentration-to-dose (C/D) ratio. In total, 269 patients were included and assigned to the following genotype-predicted phenotype subgroups: CYP2D6 poor metabolizers (PMs, n = 23), intermediate metabolizers (IMs, n = 121), normal metabolizers (NMs, n = 120) and ultrarapid metabolizers (UMs, n = 5). Multiple linear regression analysis revealed a 95% higher duloxetine C/D ratio in PMs compared with NMs (p = 0.009). Patients ≥65 years had a 56% higher C/D ratio than younger patients (p = 0.01), while women had a 46% higher C/D ratio than men (p = 0.04). In conclusion, the CYP2D6 PM phenotype is associated with a twofold higher concentration at recommended dosing compared with the NM phenotype. CYP2D6 PM females above 65 years are at particular risk of high duloxetine levels as they may obtain a threefold higher C/D ratio compared with younger, male NMs.
度洛西汀主要经细胞色素 P450（CYP）1A2 和 CYP2D6 代谢。本研究旨在探讨 CYP2D6 基因型对度洛西汀血药浓度的影响，以年龄和性别为协变量进行校正。患者从治疗药物监测服务中进行回顾性纳入。采用多元线性回归分析，研究 CYP2D6 基因型、年龄和性别对度洛西汀浓度与剂量（C/D）比值的影响。共纳入 269 例患者，按照 CYP2D6 基因型预测表型分为以下亚组：CYP2D6 弱代谢者（PMs，n=23）、中间代谢者（IMs，n=121）、正常代谢者（NMs，n=120）和超快代谢者（UMs，n=5）。多元线性回归分析显示，PM 患者的度洛西汀 C/D 比值比 NM 患者高 95%（p=0.009）。≥65 岁的患者比年轻患者的 C/D 比值高 56%（p=0.01），而女性比男性的 C/D 比值高 46%（p=0.04）。总之，与 NM 表型相比，CYP2D6 PM 表型在推荐剂量下的浓度高两倍。65 岁以上的 CYP2D6 PM 女性，与年轻的男性 NM 相比，可能会出现三倍以上的高度洛西汀水平，因此存在较高的度洛西汀水平风险。
