Endoxifen

Endoxifen is an active metabolite of tamoxifen, a selective estrogen receptor modulator (SERM) used primarily for the treatment of hormone receptor-positive breast cancer. Endoxifen is formed through the action of the cytochrome P450 enzyme CYP2D6. It is considered to be one of the most potent anti-estrogenic metabolites of tamoxifen and is thought to contribute significantly to the therapeutic efficacy of the drug.

Unlike tamoxifen, which is a prodrug, endoxifen is an active molecule in itself. It exhibits a much higher affinity for the estrogen receptor compared to tamoxifen and has been shown to be more effective in inhibiting estrogen-dependent cell growth in vitro.

The formation of endoxifen is highly dependent on CYP2D6 activity. Individuals with genetic variations that result in reduced CYP2D6 activity (poor metabolizers) may produce lower levels of endoxifen, potentially leading to reduced therapeutic effectiveness of tamoxifen. This has led to research into alternative therapies or strategies for patients who are poor metabolizers of tamoxifen. Conversely, ultra-rapid metabolizers may produce higher levels of endoxifen.

Research into endoxifen is ongoing, with studies exploring its potential as a direct therapeutic agent, bypassing the need for CYP2D6 metabolism and potentially providing a more consistent and predictable response in all patients, regardless of their CYP2D6 genotype. Its use as a biomarker to predict response to tamoxifen therapy is also being investigated.