Selective Estrogen Receptor Modulators (SERMs)

Mechanism

Mechanism of Action

SERMs are non-steroidal molecules that act by competitively interacting with nuclear estrogen receptors (ERα and ERβ) in various target tissues, selectively inducing agonist or antagonist effects depending on the tissue.

Physiology of Tissue Selectivity of SERMs

By binding to the estrogen receptor, SERM induces a distinct three-dimensional conformation of helix 12 of the ER receptor. This structural alteration selectively exposes or blocks interaction surfaces with nuclear transcription coregulators:
1. Tamoxifen: Acts as an estrogen antagonist in breast tissue (blocking estrogen-dependent tumor cell proliferation), but behaves as a partial estrogen agonist in the endometrium (stimulating endometrial proliferation) and in bone tissue (decreasing bone resorption).
2. Raloxifene: Acts as an antagonist in the breast tissue and endometrium (it does not induce endometrial hyperplasia or associate gynecological tumor risk), and behaves as a partial agonist in the skeletal system (stabilizing bone density) and in lipid metabolism.

Pharmacokinetics

Pharmacokinetics

• Route of administration: Oral.
• Tamoxifen: Rapid and complete absorption. It undergoes extensive hepatic metabolism by the polymorphic enzyme CYP2D6 and by CYP3A4 to generate its most potent biologically active metabolites: N-desmethyltamoxifen and Endoxifen (4-hydroxy-N-desmethyltamoxifen), which has a binding affinity for the ER receptor 100 times higher than unchanged tamoxifen. Prolonged plasma half-life of about 5 to 7 days for tamoxifen and up to 14 days for its metabolites by enterohepatic recirculation.
• Raloxifene: Rapid oral absorption of 60%, but undergoes massive and accelerated intestinal and hepatic first-pass glucuronidation, achieving a real net bioavailability of only 2%. It is not a significant substrate of hepatic CYP450 cytochromes. Elimination half-life of about 28 to 32 hours.
• Excretion: Mainly biliary and fecal for both drugs.

Indicators and dose

Indications

• Tamoxifen: Adjuvant and first-line treatment of estrogen receptor-positive (ER+) primary or metastatic breast cancer in pre- and postmenopausal women. Chemoprevention of breast cancer in high-risk women.
• Raloxifene: Prevention and treatment of postmenopausal osteoporosis. Reduction in the risk of invasive breast cancer in postmenopausal women with osteoporosis or at high risk of developing malignant pathology.

Dosage

• Tamoxifen: 20 mg orally once a day uninterrupted for a standard period of 5 to 10 years in breast cancer.
• Raloxifene: 60 mg orally once daily continuously for the treatment or prevention of postmenopausal osteoporosis.

Pregnancy and Breastfeeding

FDA Category X for both. Highly teratogenic; They associate malformations of the craniofacial, genital tract and musculoskeletal system. Absolutely contraindicated. It is unknown if they are excreted in breast milk, but by inhibiting the effect of estrogens they drastically reduce lactogenesis in the immediate postpartum period.

Security

Contraindications

Tamoxifen

• Confirmed personal history of deep vein thrombosis (DVT) or pulmonary embolism (PE).
• Concomitant treatment with strong inhibitors of the CYP2D6 enzyme.
• Confirmed pregnancy and active breastfeeding.
• History of severe atypical endometrial hyperplasia.

Raloxifene

• Personal history of active or past venous thromboembolic events.
• Women with the potential to become pregnant (contraindicated in childbearing age).
• Planned or active prolonged immobilization.
• Hepatic failure or underlying cholestasis of any etiology.

Adverse Effects (ADR)

Interactions of Tamoxifen and CYP2D6 Polymorphism

Critical Interaction: CYP2D6 Inhibitors and Oncological Treatment Failure

Since the conversion of tamoxifen into its most potent active metabolite, endoxifen, depends obligately on the enzyme CYP2D6, the co-administration of drugs that are potent inhibitors of this enzyme can nullify the protective antitumor therapeutic effect of tamoxifen, increasing the rate of breast cancer recurrence alarmingly. The simultaneous use of the following drugs should be strictly avoided:

• Potent SSRI antidepressants: Paroxetine, Fluoxetine.
• Selective serotonin and norepinephrine reuptake inhibitors: Duloxetine.
• Antiarrhythmics: Quinidine.

If a patient being treated with tamoxifen requires therapy for hot flashes or depression, Venlafaxine or Citalopram (drugs with minimal inhibition profile on CYP2D6) should preferably be used.