Current evidence supporting solanidine and its metabolites as biomarkers of CYP2D6 activity.

CYP2D6 is a key determinant of drug metabolism and interindividual variability in drug response. Although genotyping is increasingly used in clinical practice, it cannot fully capture in vivo enzyme activity, which is strongly influenced by environmental and clinical factors causing phenoconversion. This limitation highlights the need for noninvasive biomarkers that provide a functional, real-time assessment of CYP2D6 activity. Over the past decade, solanidine-a potato-derived steroidal alkaloid-and its CYP2D6-dependent metabolites, especially 4-hydroxysolanidine and 3,4-seco-solanidine-3,4-dioic acid, have emerged as promising candidates. Initially identified through untargeted metabolomics, these compounds consistently reflect CYP2D6 activity across diverse populations and analytical methods. Poor metabolizers exhibit marked accumulation of solanidine and near absence of its metabolites. These biomarkers are sensitive to pharmacological CYP2D6 inhibition and correlate with established probe drugs, capturing both genetic and environmental determinants of enzyme activity, including phenoconversion and rare variants missed by genotyping. Despite challenges related to dietary exposure and analytical standardization, current evidence supports solanidine and its metabolites as practical, noninvasive biomarkers that complement pharmacogenetic testing in precision medicine. This minireview synthesizes the current evidence on their identification, functional relevance, and emerging applications in CYP2D6 phenotyping. SIGNIFICANCE STATEMENT: Solanidine and its CYP2D6-dependent metabolites emerge as promising noninvasive biomarkers of CYP2D6 activity, enabling real-time functional phenotyping beyond genotype alone. They reliably identify poor metabolizers and detect phenoconversion in complex clinical settings, offering a practical complement to pharmacogenetics and advancing precision dosing in populations where traditional phenotyping is impractical. However, current evidence suggests limited discrimination between adjacent phenotype groups, particularly intermediate, normal, and ultrarapid metabolizers, highlighting the need for further validation studies.