endoxifen

Endoxifen, chemically known as 4-hydroxy-N-desmethyl-tamoxifen, is an active metabolite of the selective estrogen receptor modulator tamoxifen. It contributes to the antiestrogenic effects of tamoxifen in breast tissue and to estrogenic or mixed effects in other tissues, depending on the context. Endoxifen is one of the major metabolites believed to play a key role in the therapeutic activity of tamoxifen for estrogen receptor–positive breast cancer.

Biosynthesis and pharmacokinetics occur mainly in the liver through the cytochrome P450 system. Tamoxifen is first N-demethylated to N-desmethyl-tamoxifen, which is then hydroxylated to endoxifen, a reaction largely mediated by CYP2D6. Endoxifen has a relatively long persistence in the body and tends to accumulate with ongoing therapy. Plasma concentrations vary among individuals, influenced by CYP2D6 genetic variants as well as concurrent medications that inhibit or induce the enzyme.

Pharmacologically, endoxifen binds estrogen receptors ERα and ERβ, acting as an antagonist in breast tissue to inhibit tumor cell proliferation, with tissue-selective effects that can differ in other organs. Its activity is often discussed in the context of tamoxifen’s overall pharmacology, as endoxifen is considered a major contributor to the drug’s clinical efficacy.

Clinical significance and pharmacogenomics note that higher endoxifen exposure has been associated in some studies with better treatment outcomes in ER-positive breast cancer, though findings are not uniformly consistent. Individuals with reduced CYP2D6 activity or those taking strong CYP2D6 inhibitors may have lower endoxifen levels, potentially affecting efficacy. In such cases, alternative antidepressants or treatment adjustments may be considered to preserve tamoxifen activity.

Endoxifen is not typically prescribed as a standalone therapy; it is studied as a key active metabolite in the context of tamoxifen pharmacology and personalized medicine. Safety considerations largely reflect the known adverse effects of tamoxifen, with specific data for endoxifen alone being more limited.