Drug-Drug Interaction between Toosendanin and Tamoxifen and Its Potential Mechanism

INTRODUCTION: Toosendanin has shown anticancer activity in various malignancies, including gynecological cancers. As tamoxifen is a cornerstone therapy for breast and ovarian cancers, this study investigated how toosendanin alters its pharmacokinetics, with the goal of assessing interaction risks and supporting drug development. METHODS: A pharmacokinetic study was performed in female Sprague-Dawley rats. The rats received an oral dose of tamoxifen (10 mg/kg), with or without pretreatment with toosendanin (30 or 60 mg/kg). Plasma concentrations of tamoxifen were determined by LC-MS/MS. The effects of toosendanin on the metabolic stability of tamoxifen and cytochrome P450 enzyme (CYP450) activity were investigated using liver microsomes. RESULTS: Toosendanin significantly altered the pharmacokinetic profile of tamoxifen. Concomitant administration of toosendanin (30 and 60 mg/kg) resulted in a dose-dependent increase in the maximum plasma concentration of tamoxifen from 120.67 ± 7.50 to 186.67 ± 6.44 and 235.00 ± 15.96 µg/L, respectively. The half-life was prolonged from 12.55 ± 0.57 to 14.46 ± 0.96 and 16.55 ± 1.02 h, while the clearance rate decreased from 4.92 ± 0.24 to 3.04 ± 0.14 and 2.10 ± 0.07 L/h/kg, respectively. In vitro studies further revealed that toosendanin inhibited the metabolic stability of tamoxifen, as evidenced by a reduction in its intrinsic clearance from 45.36 ± 1.92 to 34.48 ± 1.92 and 28.44 ± 1.21 µL/min/mg protein. Furthermore, toosendanin exhibited a half-maximal inhibitory concentration of 11.50 µm for CYP2D6 activity. CONCLUSION: This study demonstrates that toosendanin alters the pharmacokinetics of tamoxifen, likely by inhibiting its metabolic stability and CYP2D6 activity. This interaction leads to a potentially significant pharmacokinetic risk when toosendanin is co-administered with tamoxifen, potentially potentiating its exposure.