TAMOXIFEN EBEWE

Tamoxifen is a non-steroidal antiestrogen used to treat estrogen receptor positive breast cancers as well as prevent the incidence of breast cancer in high risk populations. 1, 15, 16 Tamoxifen is used alone or as an adjuvant in these treatments. 15, 16 Tamoxifen may no longer be the preferred treatment for these types of cancers as patients generally have better survival, side effect profiles, and compliance with anastrozole.

Tamoxifen was granted

FDA approval on 30 December 1977.

Tamoxifen is indicated to treat estrogen receptor positive metastatic breast cancer in adults, as an adjuvant in the treatment of early stage estrogen receptor positive breast cancer in adults, to reduce the risk of invasive breast cancer after surgery and radiation in adult women with ductal carcinoma in situ.

Tamoxifen is a selective estrogen receptor modulator that inhibits growth and promotes apoptosis in estrogen receptor positive tumors. 1, 8 It has a long duration of action as the active metabolite N-desmethyltamoxifen has a half life of approximately 2 weeks. 15, 16 It has a narrow therapeutic index as higher doses can lead to breathing difficulty or convulsions. 15, 16 Tamoxifen administration is also associated with an increased incidence of uterine malignancies. 15, 16.

Estrogen receptor Antagonist Agonist Estrogen receptor beta Antagonist Agonist Protein kinase C Inhibitor + 1 more target.

An oral dose of 20 mg reaches a C max of 40ng/mL with a T max of 5 hours. 15, 16 The metabolite N-desmethyltamoxifen reaches a C max of 15ng/mL. 15, 16 10 mg of tamoxifen Oral twice daily for 3 months results in a C ss of 120ng/mL and a C ss of 336ng/mL. 15, 16.

The volume of distribution of tamoxifen is approximately 50-60 L/kg.

Tamoxifen can by hydroxylated to α-hydroxytamoxifen which is then glucuronidated or undergoes sulfate conjugation by sulfotransferase 2A1. 4, 6 Tamoxifen can also undergo N-oxidation by flavin monooxygenases and 3 to tamoxifen N-oxide. 4, 6, 7 Tamoxifen is N-dealkylated to N-desmethyltamoxifen by CYP2D6, CYP1A1, CYP1A2, CYP3A4, CYP1B1, CYP2C9, CYP2C19, and CYP3A5. 3, 4, 5, 6, 7 N-desmethyltamoxifen can be sulfate conjugated to form N-desmethyltamoxifen sulfate, 4-hydroxylated by CYP2D6 to form endoxifen, or N-dealkylated again by CYP3A4 and CYP3A5 to N,N-didesmethyltamoxifen. 4, 5, 13 N,N-didesmethyltamoxifen undergoes a substitution reaction to form tamoxifen metabolite Y, followed by ether cleavage to metabolite E, which can then be sulfate conjugated by sulfotransferase 1A1 and 1E1 or O-glucuronidated. 13, 14 Tamoxifen can also by 4-hydroxylated by CYP2D6, CYP2B6, CYP3A4, CYP2C9, and CYP2C19 to form 4-hydroxytamoxifen. 3, 4, 5, 6 4-hydroxytamoxifen can undergo glucuronidation by UGT1A8, UGT1A10, UGT2B7, and UGT2B17 to tamoxifen glucuronides, sulfate conjugation by sulfotransferase 1A1 and 1E1 to 4-hydroxytamoxifen sulfate, or N-dealkylation by CYP3A4 and CYP3A5 to endoxifen. 4, 5 Endoxifen undergoes demethylation to norendoxifen, a reversible sulfate conjugation reaction via sulfotransferase 1A1 and 1E1 to 4-hydroxytamoxifen sulfate, sulfate conjugation via sulfotransferase 2A1 to 4-endoxifen sulfate, or glucuronidation via UGT1A8, UGT1A10, UGT2B7, or UGT2B15 to tamoxifen glucuronides. 13, 4, 5 Hover over products below to view reaction partners Tamoxifen N-Desmethyltamoxifen N,N-didesmethyltamoxifen Tamoxifen Metabolite Y Tamoxifen Metabolite E Tamoxifen Metabolite E Sulfate Conjugate Tamoxifen Metabolite E Glucuronide Endoxifen (4-hydroxy-N-desmethyltamoxifen) Norendoxifen (4-hydroxy-N,N-didesmethyltamoxifen) 4-hydroxytamoxifen sulfate 4-endoxifen Sulfate Tamoxifen Glucuronides N-desmethyltamoxifen Sulfate α-hydroxytamoxifen α-tamoxifen Sulfate α-hydroxytamoxifen Glucuronide Tamoxifen N-oxide 4-Hydroxytamoxifen Tamoxifen Glucuronides 4-hydroxytamoxifen sulfate Endoxifen (4-hydroxy-N-desmethyltamoxifen) Norendoxifen (4-hydroxy-N,N-didesmethyltamoxifen) 4-endoxifen Sulfate Tamoxifen Glucuronides Endoxifen (4-hydroxy-N-desmethyltamoxifen) Norendoxifen (4-hydroxy-N,N-didesmethyltamoxifen) 4-hydroxytamoxifen sulfate 4-endoxifen Sulfate Tamoxifen Glucuronides.

Tamoxifen is mainly eliminated in the feces. 15, 16 Animal studies have shown 75% of radiolabelled tamoxifen recovered in the feces, with negligible collection from urine.

However, 1 human study showed 26.7% recovery in the urine and 24.7% in the feces.

The terminal elimination half-life of tamoxifen is 5-7 days, while the half-life of N-desmethyltamoxifen, the primary circulating metabolite, is approximately 14 days. 15, 16.

The clearance of tamoxifen was 189 mL/min in a study of six postmenopausal women.

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High doses of tamoxifen in animals lead to respiratory difficulty and convulsions. 15, 16 High doses in advanced metastatic cancer patients resulted in acute neurotoxicity seen by tremor, hyperreflexia, unsteady gait, and dizziness. 15, 16 Patients experiencing and overdose should be given supportive treatment as no specific treatment for overdose is suggested. 15, 16.