Tamoxifen citrate Action

Tamoxifen citrate is used to treat breast cancer that has spread to other parts of the body , to treat breast cancer in certain patients after surgery and radiation therapy, and to reduce the chances of breast cancer in high-risk patients.


1.Mechanism of action
Tamoxifen citrate  competitively binds to estrogen receptors on tumor cells and other tissue targets, producing a nuclear complex that decreases DNA synthesis and inhibits estrogen effects. It is a nonsteroidal agent with potent antiestrogenic properties which compete with estrogen for binding sites in breast and other tissues. Tamoxifen citrate  causes cells to remain in the G0 and G1 phases of the cell cycle. Because it prevents (pre)cancerous cells from dividing but does not cause cell death, Tamoxifen citrate  is cytostatic rather than cytocidal.

Tamoxifen citrate  itself is a prodrug, having relatively little affinity for its target protein, the estrogen receptor. It is metabolized in the liver by the cytochrome P450 isoform CYP2D6 and CYP3A4 into active metabolites such as 4-hydroxytamoxifen (afimoxifene) and N-desmethyl-4-hydroxytamoxifen (endoxifen) which have 30-100 times more affinity with the estrogen receptor than Tamoxifen citrate  itself. These active metabolites compete with estrogen in the body for binding to the estrogen receptor. In breast tissue, 4-hydroxytamoxifen acts as an estrogen receptor antagonist so that transcription of estrogen-responsive genes is inhibited.
Tamoxifen citrate  binds to estrogen receptor (ER) which in turn interacts with DNA. The ER/tamoxifen complex recruits other proteins known as co-repressors to stop genes being switched on by estrogen. Some of these proteins include NCoR and SMRT. Tamoxifen citrate  function can be regulated by a number of different variables including growth factors. Tamoxifen citrate  needs to block growth factor proteins such as ErbB2/HER2 because high levels of ErbB2 have been shown to occur in Tamoxifen citrate  resistant cancers. Tamoxifen citrate  seems to require a protein PAX2 for its full anticancer effect. In the presence of high PAX2 expression, the tamoxifen/estrogen receptor complex is able to suppress the expression of the pro-proliferative ERBB2 protein. In contrast, when AIB-1 expression is higher than PAX2, tamoxifen/estrogen receptor complex upregulates the expression of ERBB2 resulting in stimulation of breast cancer growth.

2.Absorption and Distribution
Following a single oral dose of 20 mg Tamoxifen citrate , an average peak plasma concentration of 40 ng/mL (range 35 to 45 ng/mL) occurred approximately 5 hours after dosing. The decline in plasma concentrations of Tamoxifen citrate  is biphasic with a terminal elimination half-life of about 5 to 7 days. The average peak plasma concentration of N-desmethyl Tamoxifen citrate  is 15 ng/mL (range 10 to 20 ng/mL). Chronic administration of 10 mg Tamoxifen citrate  given twice daily for 3 months to patients results in average steady-state plasma concentrations of 120 ng/mL (range 67-183 ng/mL) for Tamoxifen citrate  and 336 ng/mL (range 148-654 ng/mL) for N-desmethyl Tamoxifen citrate . The average steady-state plasma concentrations of Tamoxifen citrate  and N-desmethyl Tamoxifen citrate  after administration of 20 mg Tamoxifen citrate  once daily for 3 months are 122 ng/mL (range 71-183 ng/mL) and 353 ng/mL (range 152-706 ng/mL), respectively. After initiation of therapy, steady-state concentrations for Tamoxifen citrate  are achieved in about 4 weeks and steady-state concentrations for N-desmethyl Tamoxifen citrate  are achieved in about 8 weeks, suggesting a half-life of approximately 14 days for this metabolite. In a steady-state, crossover study of 10 mg Tamoxifen citrate tablets given twice a day vs. a 20 mg Tamoxifen citrate tablet given once daily, the 20 mg Tamoxifen citrate tablet was bioequivalent to the 10 mg tamoxifen citrate tablets.

3.Metabolism

Tamoxifen citrate  is extensively metabolized after oral administration. N-desmethyl Tamoxifen citrate  is the major metabolite found in patients' plasma. The biological activity of N-desmethyl Tamoxifen citrate  appears to be similar to that of Tamoxifen citrate . 4-Hydroxytamoxifen and a side chain primary alcohol derivative of Tamoxifen citrate  have been identified as minor metabolites in plasma. Tamoxifen citrate  is a substrate of cytochrome P-450 3A, 2C9 and 2D6, and an inhibitor of P-glycoprotein.

4.Excretion


Studies in women receiving 20 mg of 14C Tamoxifen citrate  have shown that approximately 65% of the administered dose was excreted from the body over a period of 2 weeks with fecal excretion as the primary route of elimination. The drug is excreted mainly as polar conjugates, with unchanged drug and unconjugated metabolites accounting for less than 30% of the total fecal radioactivity.