Unveiling the Impact of Morphine on Tamoxifen Metabolism in Mice in vivo

Abstract

Background: Tamoxifen is used to treat breast cancer and cancer recurrences. After administration, tamoxifen is converted into two more potent antitumor compounds, 4OH-tamoxifen and endoxifen by the CYP3A4/5 and 2D6 enzymes in human. These active compounds are inactivated by the same UDP-glucuronosyltransferase isoforms as those involved in the metabolism of morphine. Importantly, cancer-associated pain can be treated with morphine, and the common metabolic pathway of morphine and tamoxifen suggests potential clinically relevant interactions. Methods: Mouse liver microsomes were used to determine the impact of morphine on 4OH-tamoxifen metabolism in vitro. For in vivo experiments, female mice were first injected with tamoxifen alone and then with tamoxifen and morphine. Blood was collected, and LC-MS/MS was used to quantify tamoxifen, 4OH-tamoxifen, N-desmethyltamoxifen, endoxifen, 4OH-tamoxifen-glucuronide, and endoxifen-glucuronide. Results: In vitro, we found increased K m values for the production of 4OH-tamoxifen-glucuronide in the presence of morphine, suggesting an inhibitory effect on 4OH-tamoxifen glucuronidation. Conversely, in vivo morphine treatment decreased 4OH-tamoxifen levels in the blood while dramatically increasing the formation of inactive metabolites 4OH-tamoxifen-glucuronide and endoxifen-glucuronide. Conclusions: Our findings emphasize the need for caution when extrapolating results from in vitro metabolic assays to in vivo drug metabolism interactions. Importantly, morphine strongly impacts tamoxifen metabolism in mice. It suggests that tamoxifen efficiency could be reduced when both drugs are co-administered in a clinical setting, e.g., to relieve pain in breast cancer patients. Further studies are needed to assess the potential for tamoxifen-morphine metabolic interactions in humans.

The immunotherapy candidate TNFSF4 may help the induction of a promising immunological response in breast carcinomas

“…Improving cancer-related immune resistance is mainly achieved through immune checkpoint blockade therapy, and multiple immune checkpoint-targeting agents have been identified and clinically applied to treat lung cancer, esophageal cancer, melanoma, etc. Therapeutic targets include but are not limited to PD-L1 (CD274), PD-L2 (PDCD1LG2), CD80, CD86, and CD70, and novel applied therapies have shown promise in lung cancer and melanoma treatment 6 – 10 . However, how immune checkpoint blockade therapy acts in the breast cancer treatment process and what checkpoint may be targeted to achieve benefits are totally unknown.…”

Relationship of micro-RNA, mRNA and eIF Expression in Tamoxifen-Adapted MCF-7 Breast Cancer Cells: Impact of miR-1972 on Gene Expression, Proliferation and Migration

“…The result for the pathway leading to morphine addiction seems hard to explain; however, several effects of tamoxifen on morphine responses and vice versa have been published. For example, glucuronidation of morphine and tamoxifen occurs by the same enzymes in mice, which could lead to reduced tamoxifen efficiency [ 57 ]. In mice, estrogens and tamoxifen also modified methadone responses [ 58 ].…”