Nutrimetric validation of solanidine as dietary-derived CYP2D6 activity marker in vivo

CYP2D6 is involved in the metabolism of many drugs. Its activity is affected by pharmacogenetic variability leading to highly polymorphic phenotypes between individuals, affecting safety and efficacy of drugs. Recently, solanidine, a steroidal alkaloid from potatoes, and its metabolites, has been identified as a dietary-derived activity marker for CYP2D6. The intraday variability in plasma within individuals has not been studied yet in healthy subjects. As part of a CYP phenotyping cocktail study with 20 healthy participants, plasma concentrations of solanidine, 4-OH-solanidine and 3,4-secosolanidine-3,4-dioic acid (SSDA) were determined using a sensitive LC-MS method in urine and in plasma at time points 0, 2.5, 5, 8 and 24 hours after intake of test substances. The participants were phenotyped for CYP2D6 with oral metoprolol (12.5 mg) with 15 plasma sampling points over 24 hours (DRKS00028922). Metabolic ratios (MR) of metabolite to parent plasma concentrations were formed from single time points and the AUC. All participants were genotyped for CYP2D6. The intra-individual variability of the CYP2D6 metabolite SSDA was highly stable with a median SD of 11.62 % over 24 hours. MR SSDA/solanidine was more variable (median SD 31.90 %) but correlated significantly at all measured time points with AUC MR α-OH-metoprolol/metoprolol. The AUC MR SSDA/solanidine showed a significant linear relationship with the genetically predicted CYP2D6 activity score. This study substantiates the MR SSDA/solanidine as CYP2D6 activity marker. The high correlation with metoprolol MR indicates a valid prediction of the CYP2D6 phenotype at any time point during the study day.