Solanidine-derived CYP2D6 phenotyping elucidates phenoconversion in multimedicated geriatric patients

Area of Science:

• Pharmacogenomics
• Clinical Chemistry

Background:

• Phenoconversion, a mismatch between predicted and actual drug metabolism, hinders personalized medicine.
• Geriatric patients often have multimorbidity and polypharmacy, increasing the risk of adverse drug events due to variable drug metabolism.

Purpose of the Study:

• To detect and quantify phenoconversion in elderly, multimorbid patients using specific solanidine metabolites as biomarkers for cytochrome P450 2D6 (CYP2D6) activity.
• To assess the utility of these biomarkers in a high-polypharmacy setting.

Main Methods:

• Collected blood samples and medication data from geriatric patients undergoing physician consultation.
• Quantified solanidine and its metabolites (including 3,4-seco-solanidine-3,4-dioic acid [SSDA]) using liquid chromatography/tandem mass spectrometry for CYP2D6 phenotyping.
• Assigned CYP2D6 activity scores (AS) based on genotyping and compared them with phenotyping results.

Main Results:

• Analyzed data from 88 geriatric patients (median age 83 years, 70.5% female) on a median of 15 medications.
• The SSDA/solanidine metabolic ratio significantly correlated with genotyping-derived AS (P < .001), effectively identifying poor CYP2D6 metabolizers.
• Each additional CYP2D6 substrate/inhibitor reduced the predicted AS by 0.53 in patients with functional CYP2D6 variants, after adjusting for covariates (R² = 0.242).

Conclusions:

• Diet-derived biomarkers for CYP2D6 phenotyping can elucidate phenoconversion in geriatric patients with multimorbidity and polypharmacy.
• These findings support the development of a bedside method for measuring CYP2D6 activity, crucial for personalized drug prescribing in complex patient populations.