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

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.

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.

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.

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.