Solanidine-derived CYP2D6 phenotyping elucidates phenoconversion in multimedicated geriatric patients

IF 3.1 3区医学 Q2 PHARMACOLOGY & PHARMACY

British journal of clinical pharmacology Pub Date : 2025-05-29 DOI:10.1111/bcp.70004

Jens Andreas Sarömba, Julian Peter Müller, Jolanta Tupiec, Anjali Roeth, Berkan Kurt, Florian Kahles, Thea Laurentius, Cornelius Bollheimer, Julia C. Stingl, Katja S. Just

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引用次数: 0

Abstract

Aims

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.

Methods

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.

Results

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 (R² = 0.242).

Conclusions

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.

查看原文本刊更多论文

solanidine衍生的CYP2D6表型阐明了多种药物治疗的老年患者的表型转化

目的表型转化是一种基因型-表型不匹配，挑战了个性化医疗的成功实施。本研究的目的是检测和确定表型转化，使用茄碱代谢物3,4-次-茄碱-3,4-二酸（SSDA）和4-羟基茄碱作为饮食来源的细胞色素P450 2D6 （CYP2D6）生物标志物，在老年、多病、高水平多药的队列中。方法在会诊时采集老年、多药患者的血样及相关资料（CT: NCT05247814）。通过液相色谱/串联质谱法测定茄碱及其代谢物，并用于CYP2D6表型分析。进行CYP2D6基因分型和活性评分（AS）。评估完全的药物摄入情况。计算了通过基因分型预测的AS的移位，并测量了表型。结果对88例用药记录完整的患者进行了索拉尼定及其代谢物检测。患者中位年龄为83岁（四分位间距[IQR] 77-87），女性占多数（70.5%,n = 62）。患者平均服用15种药物（IQR 12-17）。SSDA/茄碱代谢比与基因型衍生的AS显著相关（P < .001），并清楚地检测到代谢不良者。在校正了年龄、性别、Charlson共病指数和肾小球滤过率的模型中，每增加一个CYP2D6底物/抑制剂，编码功能性CYP2D6变异的患者的预期AS显著降低0.53（95%置信区间0.85-0.21）点（R2 = 0.242）。结论通过测量饮食来源的生物标志物对CYP2D6活性进行表型分析，阐明了老年患者的表型转化。这些结果可能为验证和建立一种床边方法来测量多种疾病患者的CYP2D6活性，从而成功应用个性化药物处方提供前提条件。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

British journal of clinical pharmacology 医学-药学

CiteScore

6.30

自引率

8.80%

发文量

419

审稿时长

1 months

期刊介绍： Published on behalf of the British Pharmacological Society, the British Journal of Clinical Pharmacology features papers and reports on all aspects of drug action in humans: review articles, mini review articles, original papers, commentaries, editorials and letters. The Journal enjoys a wide readership, bridging the gap between the medical profession, clinical research and the pharmaceutical industry. It also publishes research on new methods, new drugs and new approaches to treatment. The Journal is recognised as one of the leading publications in its field. It is online only, publishes open access research through its OnlineOpen programme and is published monthly.