Endoxifen
The potent active metabolite of tamoxifen (4-hydroxy-N-desmethyltamoxifen), formed via CYP2D6. Given directly it bypasses variable tamoxifen metabolism and is under clinical study for breast cancer and mania.
01 Overview
Endoxifen is the major pharmacologically active metabolite of tamoxifen, produced mainly by the liver enzyme CYP2D6. It is roughly 30-100 times more potent than tamoxifen itself at the oestrogen receptor, so patients who are poor CYP2D6 metabolisers derive less benefit from tamoxifen.
Giving endoxifen directly avoids this metabolic variability and has been studied for ER-positive breast cancer and, separately, as a protein kinase C inhibitor in bipolar mania. It represents the 'business end' of tamoxifen for anti-estrogen effect.
02 Mechanism
Active SERM metabolite: high-affinity oestrogen receptor antagonist in breast tissue; also inhibits protein kinase C at higher concentrations, independent of CYP2D6 activation.
03 Dosing
| Tier | Dose | Route | Notes |
|---|---|---|---|
| Trial dose | 1–8 mg/day | Oral | Doses studied in breast cancer and mania trials. |
04 Effects
| Effect | Magnitude | Evidence | |
|---|---|---|---|
| Potent estrogen antagonismDirectly antagonises the breast oestrogen receptor without needing CYP2D6 activation. | 30-100x tamoxifen potency | Clinical | |
| Consistent exposure across metabolisersDelivers active drug regardless of the patient's CYP2D6 genotype. | Bypasses CYP2D6 variability | Clinical |
05 Side effects
| Effect | Severity | Frequency | Evidence | Countermeasures |
|---|---|---|---|---|
| Hot flashesVasomotor symptoms typical of SERMs. | Mild | Common | Clinical | |
| Venous thromboembolismTriphenylethylene class clotting risk shared with tamoxifen. | Severe | Rare | Clinical |