Solanidine Metabolites as Diet‐Derived Biomarkers of CYP2D6‐Mediated Tamoxifen Metabolism in Breast Cancer Patients

Abstract

Tamoxifen is an important antiestrogen for the treatment of hormone receptor‐positive breast cancer and undergoes bioactivation by CYP2D6 to its active metabolite endoxifen. Genetic variation in CYP2D6 has been linked to endoxifen levels during tamoxifen therapy. Recent studies have suggested solanidine, a glycoalkaloid phytochemical in potatoes, undergoes CYP2D6‐mediated metabolism to 4‐OH‐solanidine (m/z 414) and 3,4‐seco‐solanidine‐3,4‐dioic acid (SSDA; m/z 444). Using a retrospective cohort of 1,032 breast cancer patients on tamoxifen therapy, we examined the association of solanidine metabolites with CYP2D6 activity and its correlation with tamoxifen metabolism. Solanidine, 4‐OH‐solanidine, or SSDA was detected in 99.7% (N = 1,029) of plasma samples. Decreased solanidine metabolite ratios were found in CYP2D6 intermediate and poor metabolizers (P < 0.0001). Patients on CYP2D6 strong inhibitors had a 77.6% and 94.2% decrease in 4‐OH‐solandine/solanidine (P < 0.0001) and SSDA/solanidine (P < 0.0001), respectively. The ratio of endoxifen to tamoxifen was highly correlated with both 4‐OH‐solandine/solanidine (ρ = 0.3207, P < 0.0001) and SSDA/solanidine (ρ = 0.5022, P < 0.0001) ratios. Logistic regression modeling was used to determine that 4‐OH‐solanidine/solanidine and SSDA/solanidine ratios below 2.1 and 0.8, respectively, predicted endoxifen concentrations of <16 nM. In conclusion, solanidine, 4‐OH‐solanidine, and SSDA are diet‐derived biomarkers of CYP2D6 activity. Moreover, in patients on tamoxifen therapy, 4‐OH‐solanidine/solanidine and SSDA/solanidine predicted endoxifen levels including the inhibitory effects of concomitantly prescribed CYP2D6‐interacting medications. Accordingly, 4‐OH‐solanidine/solanidine or SSDA/solanidine ratio has the potential to be particularly useful prior to initiation of tamoxifen or for determining the impact of CYP2D6 drug interactions, as well as prior to switching from an aromatase inhibitor to tamoxifen.