Sarömba Jens Andreas, Müller Julian Peter, Tupiec Jolanta, Roeth Anjali, Kurt Berkan, Kahles Florian, Laurentius Thea, Bollheimer Cornelius, Stingl Julia C, Just Katja S
Institute of Clinical Pharmacology, University Hospital RWTH Aachen, Aachen, North Rhine-Westphalia, Germany.
Department of General, Visceral, Pediatric and Transplantation Surgery, University Hospital RWTH Aachen, Aachen, North Rhine-Westphalia, Germany.
Br J Clin Pharmacol. 2025 Jun;91(6):1842-1852. doi: 10.1111/bcp.70004.
Phenoconversion, a genotype-phenotype mismatch, challenges a successful implementation of personalized medicine. The aim of this study was to detect and determine phenoconversion using the solanidine metabolites 3,4-seco-solanidine-3,4-dioic acid (SSDA) and 4-OH-solanidine as diet-derived cytochrome P450 2D6 (CYP2D6) biomarkers in a geriatric, multimorbid cohort with high levels of polypharmacy.
Blood samples and data of geriatric, multimedicated patients were collected during physician counsel (CT: NCT05247814). Solanidine and its metabolites were determined via liquid chromatography/tandem mass spectrometry and used for CYP2D6 phenotyping. CYP2D6 genotyping was performed and activity scores (AS) were assigned. Complete medication intake was assessed. A shift of the AS predicted via genotyping as measured by phenotyping was calculated.
Solanidine and its metabolites were measured in 88 patients with complete documentation of drug use. Patients had a median age of 83 years (interquartile range [IQR] 77-87) and the majority (70.5%, n = 62) were female. Patients took a median of 15 (IQR 12-17) medications. The SSDA/solanidine metabolic ratio correlated significantly with the genotyping-derived AS (P < .001) and clearly detected poor metabolizers. In the model adjusted for age, sex, Charlson Comorbidity Index and estimated glomerular filtration rate each additional CYP2D6 substrate/inhibitor significantly lowered the expected AS by 0.53 (95% confidence interval 0.85-0.21) points in patients encoding functional CYP2D6 variants (R = 0.242).
Phenotyping of CYP2D6 activity by measurement of diet-derived biomarkers elucidates phenoconversion in geriatric patients. These results might serve as a prerequisite for the validation and establishment of a bedside method to measure CYP2D6 activity in multimorbid patients for successful application of personalized drug prescribing.
表型转换，即基因型与表型不匹配，对个性化医疗的成功实施构成挑战。本研究的目的是在老年多病且用药种类繁多的队列中，使用茄啶代谢物3,4-裂环茄啶-3,4-二酸（SSDA）和4-羟基茄啶作为饮食来源的细胞色素P450 2D6（CYP2D6）生物标志物来检测和确定表型转换。
在医生咨询期间收集老年多药治疗患者的血液样本和数据（临床试验注册号：NCT05247814）。通过液相色谱/串联质谱法测定茄啶及其代谢物，并用于CYP2D6表型分析。进行CYP2D6基因分型并分配活性评分（AS）。评估完整的药物摄入量。计算通过基因分型预测的AS与通过表型分析测量的AS之间的变化。
在88例有完整用药记录的患者中测量了茄啶及其代谢物。患者的中位年龄为83岁（四分位间距[IQR]77 - 87），大多数（70.5%，n = 62）为女性。患者服用的药物中位数为15种（IQR 12 - 17）。SSDA/茄啶代谢率与基因分型衍生的AS显著相关（P <.001），并能清晰检测出代谢不良者。在根据年龄、性别、Charlson合并症指数和估计肾小球滤过率进行调整的模型中，对于编码功能性CYP2D6变体的患者，每增加一种CYP2D6底物/抑制剂，预期的AS显著降低0.53（95%置信区间0.85 - 0.21）分（R = 0.242）。
通过测量饮食来源的生物标志物对CYP2D6活性进行表型分析可阐明老年患者的表型转换。这些结果可能是验证和建立一种床边方法以测量多病患者CYP2D6活性从而成功应用个性化药物处方的先决条件。
