2. What is Tamoxifen
Tamoxifen is non-steroidal SERM with tissue-specific activities for
the treatment and prevention of estrogen receptor positive
breast cancer.
Tamoxifen acts as potent estrogen antagonist in breast and blood
vessels and at some peripheral site , but as partial agonist in
uterus , bone , liver , pituitary .
3. • It bind to both ERα & Erβ
• Dosage form only orally
• Chemical Formula C26H29NO
4. Breast cancer
• Breast cancer when healthy cells change and grow out of control begin in different areas
of the breast — the ducts, the lobules, or in some cases, the tissue in between.
• It has the different types of breast cancer, including non-invasive, invasive, and
metastatic breast cancers
• One of the treat of breast cancer hormonal therapy
• Hormonal therapy, also called endocrine therapy, is an effective treatment for many
tumors that test positive for either ER or PR.
• Tamoxifen is one of hormonal therapy used like palliative and adjuvant therapy for breast
cancer for the treatment of metastatic breast cancer in women and men
6. Pharmacokinetics
• Absorption
• Bioavailable 89%
• Peak plasma time : 3-6 hr
• Distribution
• 99% albumin binding Protein
• The represent an extensive distribution to the peripheral tissues
• Area of high concentration breast , lung ,liver ,brain ,bone ,uterus
• Metabolism
• By hepatic CYP2D6, and also by CYP2C9 and CYP3A4
• Elimination
• Half live : has biphasic plasma 10 hours -7 days
• Excretion : feces , urine
7. Mechanism of action
• Tamoxifen is a nonsteroidal agent that binds to estrogen receptors (ER) in
breast tissue , but complex is unable to translocation into the nucleus for
its action of initiating transcription .
• The prolonged binding of tamoxifen to the nuclear chromatin of these
results in reduced DNA polymerase activity, impaired thymidine utilization,
blockade of estradiol uptake, and decreased estrogen response, down
regulation of estrogen receptor
• Result the complex fail to induce estrogen-responsive genes , and RNA
synthesis does not ensue
• It is likely that tamoxifen interacts with other coactivators in the tissue and
binds with different estrogen receptors.
13. Summary
• Tamoxifen is much less toxic than other anticancer drug
• Tamoxifen has been approved for primary prophylaxis of breast
cancer in high risk women
• Tamoxifen can also lead to increase pain if the tumor has
metastasized to bone
• If the patient has history with thromboembolism , we can use letrozol
• Tamoxifen help stop bone loss after menopause and lower cholesterol
levels
• Some people may not get the full benefit of tamoxifen : Abnormal
CYP2D6 enzyme , Medications that can interfere with CYP2D6
selective estrogen receptor modulators
While the weak estrogen agonist action manifests as stimulated of endometrial proliferation lowering of Gn (negative feedback) and prolactin level in postmenopausal women as well as improvement in their bone density .
Decrease LDL unchanged HDL
Tamoxifen use both women with premenopausal and postmenopausal metastatic breast cancer
Cure or prolong remission
* cytochrome P450
The prolonged binding of tamoxifen to the nuclear chromatin of these results in reduced DNA polymerase activity, impaired thymidine utilization, blockade of estradiol uptake, and decreased estrogen response. It is likely that tamoxifen interacts with other coactivators or corepressors in the tissue and binds with different estrogen receptors, ER-alpha or ER-beta, producing both estrogenic and antiestrogenic effects.
*
*Stimolation Chemoreceptor triger zone
*Estrogens improve the thickness and quality of the skin as well as the collagen content which prevents aging.
*It also helps lubricate the vagina.
The skin: Estrogens improve the thickness and quality of the skin as well as the collagen content which prevents aging.
The bones: Estrogen helps to preserve bone strength and prevent bone loss.
The liver and heart: The hormone regulates cholesterol production in the liver, helping to protect the heart and arteries.
*if use high dose of estrogen wighout progestron , produce delate menstruation break through bleeding irregular intervals
*blood coagulability increase due to induction of synthesis of clotting factor 2,7,9,10 ,
*Long-term exposure to tamoxifen induces hypersensitivity to estradiol.
*coumarin increase pt to 2-2.5 time above normal value ,
*FABRINOLYTIC activity in plasma increase due to lowering plasminogen – activator inhibitor-1 (PAI-1)
*increase plasminogen activor in endothelium
WARFARIN
Both 99% bound to albumin
Tamoxifen has a higher affinity for albumin protein
Co-administration results in in a risk of warfarin over dose
Rifampin
CYP 3A4 inducer
Reduce tamoxifen bioavailable
Prozac (anti-depressant )
CYP 2D6 competitor
Decrease the effect of tamoxifen
Endometrial hyperplasia \ cancer
the antidepressants known as serotonin-specific reuptake inhibitors
Quinidine
Blocking the activity of CYP2D6 can interfere with the activation of tamoxifen
