AbstractAimsPhenoconversion, 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.MethodsBlood 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.ResultsSolanidine 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).ConclusionsPhenotyping 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.