LC-MS/MS assay accurately discriminates CYP2D6 poor metabolizers using diet-derived solanidine biomarkers
Investigators developed and validated an LC-MS/MS method to quantify solanidine and its metabolites in plasma as minimally invasive biomarkers for CYP2D6 phenotyping. Applied to 94 Japanese participants, the assay showed marked reductions in metabolite ratios among predicted poor metabolizers, with receiver operating characteristic analysis yielding an AUC of 1.00 for perfect discrimination of this phenotype. While weak correlations were observed with tamoxifen metabolic ratios, the findings support solanidine-derived metrics as a practical, non-invasive alternative to genotyping or probe-based phenotyping. The study highlights the potential of clinical mass spectrometry to streamline pharmacogenomic testing, though broader validation across diverse populations is required.
The original study
Liquid Chromatography-Tandem Mass Spectrometry Quantification of Diet-Derived CYP2D6 Biomarkers for Clinical Phenotyping in Japanese Subjects.
- Authors
- Kumondai M, Hayashi N, Matsumoto Y, Ebata A, Sato M, Harada-Shoji N, et al.
- Journal
- Clinical and translational science
- Type
- Journal Article
- PMID
- 42473799
Original abstract
The enzymatic activity of cytochrome P450 2D6 (CYP2D6) exhibits substantial interindividual variation, which influences drug efficacy and the risk of adverse drug reactions to various therapeutics. While current protocols for CYP2D6 genotyping or CYP2D6 phenotyping provide useful information, less invasive and simpler tools are desirable for evaluating interindividual functional variety. Recently, solanidine (SND) and its metabolites have been proposed as biomarkers of CYP2D6 activity. In this study, we established a validated analytical method to quantify SND and its metabolites. Moreover, their utility in predicting CYP2D6 activity in the Japanese population was assessed. We synthesized and structurally confirmed 4-hydroxysolanidine (4-OHSND) and developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous measurement of SND, 4-OHSND, and 3,4-seco-solanidine-3,4-dioic acid (SSDA). This method was applied to plasma samples from 94 participants to investigate the CYP2D6 genotypes. The 4-OHSND to SND and SSDA to SND ratios showed substantial differences corresponding to the predicted CYP2D6 phenotype groups, with a marked reduction in poor metabolizers (PMs). Receiver operating characteristic analyses demonstrated complete discrimination of PMs (AUC = 1.00). In contrast, weak positive correlations were identified between SND biomarkers and certain tamoxifen metabolic ratios. These findings confirm the structural identity and quantitative detectability of 4-OHSND and support its potential as a practical biomarker for CYP2D6 PM detection. Although validation in larger and more diverse cohorts remains necessary, diet-derived biomarkers may represent a minimally invasive alternative to genotyping or probe-based approaches and may contribute to the broad implementation of phenotype-guided personalized medicine.