Anticancer Drugs Oncology Pharmacology Physiotherapy Tamoxifen

Tamoxifen (Mechanism of Action)

In this article we will discuss Tamoxifen (Mechanism of Action)

In this article, we will discuss Tamoxifen (Mechanism of Action). So, let’s get started.

Mechanism of Action

Tamoxifen is an estrogen agonist/antagonist. Tamoxifen competes with estrogen for binding to the estrogen
receptor, which can result in a decrease in estrogen receptor signaling-dependent growth in breast tissue. Tamoxifen has demonstrated antitumor activity against human breast cancer cell lines xenografted in mice. The drug has been shown to inhibit the induction of rat mammary carcinoma induced by dimethylbenzanthracene (DMBA) and to cause the regression of already established DMBA-induced tumors.


Absorption and Distribution

Following a single oral dose of 20 mg tamoxifen, 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 is biphasic with a terminal elimination half-life of about 5 to 7 days. The average peak plasma concentration of N-desmethyl tamoxifen, the major metabolite, is 15 ng/mL (range 10 to 20 ng/mL). Chronic administration of 10 mg tamoxifen given twice daily for 3 months to patients results in average steady-state plasma concentrations of 120 ng/mL (range 67 to 183 ng/mL) for tamoxifen and 336 ng/mL (range 148 to 654 ng/mL) for N-desmethyl tamoxifen. The average steady-state plasma concentrations of tamoxifen and N-desmethyl tamoxifen after administration of 20 mg tamoxifen once daily for 3 months are 122 ng/mL (range 71 to 183 ng/mL) and 353 ng/mL (range 152 to 706 ng/mL), respectively. The steady-state plasma concentrations of endoxifen and 4-hydroxytamoxifen are 29.1 (95% CI 24.6 to 33.6) and 3.7 (95% CI 3.3 to 4.1) ng/mL, respectively. After initiation of therapy, steady-state concentrations for tamoxifen are achieved in about 4 weeks and steady-state concentrations for N-desmethyl tamoxifen 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 tablets given twice a day vs. a 20 mg tamoxifen tablet given once daily, the 20 mg tamoxifen tablet was bioequivalent to the 10 mg tamoxifen tablets.

A pharmacokinetic study was performed in healthy perimenopausal and postmenopausal female subjects to
evaluate the bioavailability of Tamoxifen (n=30) in comparison with the commercially available tamoxifen
citrate tablets (n=33) under fasting conditions. A third arm evaluated the effect of food on Tamoxifen (n=16).
The rate and extent of absorption of Tamoxifen was found to be bioequivalent to that of tamoxifen citrate tablets under fasting conditions. There was no difference in bioavailability (Cmax and AUC) of Tamoxifen oral solution between fed and fasting states, and therefore Tamoxifen can be given without regard to meals.


Tamoxifen is extensively metabolized by CYP450 enzymes, including CYP3A, CYP2D6, CYP2C9, CYP2C19, and CYP2B6. N-desmethyltamoxifen, formed predominantly by CYP3A, is the major metabolite found in plasma. The pharmacological activity of N-desmethyltamoxifen is similar to that of tamoxifen. Endoxifen and 4-hydroxytamoxifen, identified as minor metabolites, have 100-fold greater affinity for the estrogen receptor and 30 to 100-fold greater potency in suppressing estrogen-dependent cell proliferation than tamoxifen. The polymorphic enzyme CYP2D6 is involved in the formation of endoxifen and 4-hydroxytamoxifen, and it is the key enzyme that catalyzes the formation of endoxifen from N-desmethyltamoxifen. Endoxifen concentrations may differ among patients because of various CYP2D6 genotypes. Phase 2 enzymes, such as SULT1A1, UGT2B7, and UGT1A4, are associated with tamoxifen clearance from plasma.


Studies in women receiving 20 mg of 14C tamoxifen showed 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.

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