Drug-Drug Interaction between Toosendanin and Tamoxifen and Its Potential Mechanism
Xiao He1, Yirong Zhen2, Pingfa Lin3
1Department of Pharmacy, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou, China.
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 µ
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.
Insights
Toosendanin significantly alters tamoxifen pharmacokinetics, increasing its plasma concentration and half-life. This interaction, likely due to inhibited metabolic stability and CYP2D6 activity, poses a pharmacokinetic risk when co-administered.
Area of Science:
- Pharmacology
- Drug Metabolism
- Oncology
Background:
- Toosendanin exhibits anticancer properties, particularly in gynecological cancers.
- Tamoxifen is a standard treatment for breast and ovarian cancers.
Purpose of the Study:
- To investigate the pharmacokinetic interaction between toosendanin and tamoxifen.
- To assess potential risks associated with co-administration for drug development.
Main Methods:
- Pharmacokinetic study in Sprague-Dawley rats with oral tamoxifen and toosendanin.
- LC-MS/MS analysis of plasma tamoxifen concentrations.
- In vitro investigation of toosendanin's effect on tamoxifen metabolic stability and CYP450 enzyme activity.
Main Results:
- Toosendanin caused a dose-dependent increase in tamoxifen's maximum plasma concentration and half-life.
- Tamoxifen clearance rate decreased significantly with toosendanin co-administration.
- Toosendanin inhibited tamoxifen's metabolic stability and showed inhibitory concentration for CYP2D6 activity.
Conclusions:
- Toosendanin alters tamoxifen pharmacokinetics by inhibiting metabolic stability and CYP2D6 activity.
- Co-administration presents a significant pharmacokinetic risk, potentially increasing tamoxifen exposure.
- Findings support careful consideration of toosendanin and tamoxifen co-administration in clinical settings.
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