Exploratory Evaluation of Solanidine as an Endogenous Marker for CYP2D6 ‐Mediated Drug–Drug–Gene Interactions of Venlafaxine in Koreans

CYP2D6-mediated drug-drug-gene interactions (DDGIs) are known to influence the pharmacokinetics of venlafaxine and its metabolism to O-desmethylvenlafaxine. Solanidine and 3,4-seco-solanidine-3,4-dioic acid (SSDA) have recently been investigated as candidate endogenous CYP2D6 biomarkers; however, they remain unexplored in East Asian populations, where dietary potato intake is relatively lower than that in Western populations. A prospective clinical study aimed to characterize venlafaxine DDGIs and explore the potential of solanidine as a candidate biomarker of CYP2D6 activity in healthy Korean adults. Twenty participants including 14 CYP2D6 normal metabolizers (NMs) and 6 intermediate metabolizers (IMs)-all confirmed as CYP2C19 NMs-were enrolled. Serial plasma samples for pharmacokinetic assessment were collected before and after coadministration of paroxetine, a potent CYP2D6 inhibitor. Solanidine and SSDA were also measured in plasma and urine. Compared to CYP2D6 NMs, IMs exhibited higher venlafaxine exposure but lower O-desmethylvenlafaxine exposure. Following CYP2D6 inhibition, phenotype-dependent differences in venlafaxine and O-desmethylvenlafaxine pharmacokinetics were attenuated. The metabolic ratio (MR) of plasma solanidine showed a modest positive correlation with both the MR of venlafaxine and CYP2D6 activity score. The MR of plasma solanidine decreased when CYP2D6 activity was reduced by paroxetine coadministration. These findings demonstrate phenotype-dependent DDGIs of venlafaxine and suggest the exploratory potential of solanidine as an endogenous biomarker of CYP2D6 activity in the Korean population, despite relatively lower dietary exposure to potato-derived precursors. This study provides preliminary evidence extending endogenous CYP2D6 biomarkers to an East Asian population with distinct dietary backgrounds.