Tamoxifen is a selective estrogen receptor modulator originally developed as an antifertility drug. It is now commonly used to treat and prevent breast cancer. Tamoxifen undergoes extensive metabolism and is primarily excreted through the bile. It acts as an estrogen receptor antagonist in breast tissue to inhibit cell growth. A special population study found tamoxifen may also be effective for treating brain cancers due to its ability to inhibit protein kinase C and cross the blood-brain barrier.

1. 1

2. TAMOXIFEN
Sadia Alvi
2013-Mphil-2282
2

3. CONTENTS
History
Introducing Tamoxifen
Approved Indications
Pharmacokinetics
Pharmacodynamics
Effect of Drug on Body Systems
Special Population Study
3

4. HISTORY
 Originally marketed as a an antifertility drug
and developed in the cornerstone treatment for
breast cancer.
 Approved by the FDA for postmenopausal
metastatic breast cancer in 1977
4

5. INTRODUCING TAMOXIFEN
General Use
Breast cancer treatment
and prevention
Proper Name
Tamoxifen Citrate
Chemical Formula
C26H29NO
Chemical Type
non-steroidal Selective Estrogen Receptor Modulator (SERM)
Formulation
Tamoxifen is a fine white powder and delivered orally in pill form
5

6. APPROVED INDICATIONS
Indication Year of Approval
Metastatic Breast Cancer (postmenopausal) 1977
Adjuvant Breast Cancer (postmenopausal, node-positive) 1986
Metastatic Breast Cancer (premenopausal) 1989
Adjuvant Breast Cancer (postoperative and/or chemotherapy
treatment, postmenopausal, node-negative)
1990
Metastatic Breast Cancer (male) 1993
Reduction in Breast Cancer Incidence 1998
Ductal Carcinoma in Situ (DCIS) 2000
6

7. PHARMACOKINETICS
Absorption Distribution Metabolism Excretion
7

8. ABSORPTION
20 mg Tamoxifen Oral Dose
Cmax 40 ng/mL
tmax 5 hours
Terminal t1/2 5 -7 days
Bioavailability 89%
Steady State
1 dose/day
3 months
122 ng/mL
0
5
10
15
20
25
30
35
40
45
0 1 2 3 4 5 10 20 30 40 50 60 70 80 90 100 110 120
DrugConcentration(ng/mL)
Time (h)
8

9. DISTRIBUTION
 Tamoxifen is 99% albumin-bound
in serum
 Volume of Distribution
 50 – 60 L/Kg
 This represents an extensive
distribution to the peripheral
tissues
 Areas of high concentration
 Breast
 Lung
 Liver
 Brain
 Bone
 Uterus
http://www.sciencephoto.com/media/257869/enlarge
9

10. METABOLISM
 Tamoxifen undergoes first-
pass metabolism
 Tamoxifen is metabolized
by CYP enzymes
 CYP3A
 CYP2C9
 CYP2D6
 Tamoxifen undergoes
enterohepatic circulation
 Prolongation of blood
levels and fecal excretion
Liver
CYP-450
GI Tract
Renal Excretion
Tamoxifen
Enterohepatic
circulation
Biliary Excretion
10

11. METABOLISM
 Extensive metabolism
following absorption
 Demethylation
 Hydroxylation
 Conjugation
 3 major metabolites
are produced
 N-desmethyl tamoxifen
 4-hydroxy tamoxifen
 4-hydroxy-N-desmethyl
tamoxifen (endoxifen)
11

12. EXCRETION
 Primary route of elimination
 Biliary excretion
 65% of administered drug is excreted slowly over a 2
week period
 Secondary route of elimination
 Renal excretion
 Less than 1% excreted via urine
 Excreted drug properties
 70% are polar conjugates
 Indicates high level of metabolism
12

13. PHARMACODYNAMICS
 Estrogen receptors (ER)
exist in different tissues
 Breast, brain, lung, liver,
bone, uterus
 Normal Cellular Function
 Estrogen binds to ER
 Transcription factor
synthesis
 Cell proliferation
13

14. PHARMACODYNAMICS
 Selective Estrogen Receptor
Modulator (SERM)
 A drug that targets estrogen
receptors in specific tissues
 How Tamoxifen Works
 Antagonist in breast and
brain
 No transcription
 Cell growth arrest/apoptosis
 Agonist in lung, liver, bone,
and uterus
 Normal function
14

15. EFFECT OF DRUG ON BODY SYSTEMS
 Tamoxifen also binds and
inhibits
 Protein Kinase C
 Regulates cell growth and
differentiation
 Calmodulin
 Mediates process such as
metabolism
 P-glycoproteins
 Efflux pump
 Ca2+ Channels
 Signal transduction
Tamoxifen can target mutated cancer cells that lack ER
Tamoxifen
Cell membrane fluidity
Calmodulin
PKC
DNA
ER
transcription
Apoptosis
x
15

16. EFFECT OF DRUG ON BODY SYSTEMS
 Most common side
effects (up to 25%
occurrence)
 Rarely severe enough to
require discontinuation
of treatment
 Hot flashes
 Nausea
 Vomiting
http://alturl.com/9w7jy
16

17. EFFECT OF DRUG ON BODY SYSTEMS
ADVERSE DRUG REACTIONS BENEFITS OF DRUG
 Increased risk of uterine
cancer
 Agonist in uterine ER
 Increased cell proliferation
 Increased risk of blood
clot formation
 Increase in clotting factors
 Increased risk of cataract
 Ophthalmic toxicities
 Reduced risk of
breast cancer
 ER Antagonist
 Strengthens bones
 ER Agonist
 Lower risk of heart
disease
 Increase HDL cholesterol
 Reduce LDL cholesterol
17

18. EFFECT OF DRUG ON BODY SYSTEMS
 Drug-Drug Interactions
 Coumarin-type anticoagulants (Warfarin)
 Both 99% bound to albumin
 Tamoxifen has a higher affinity for albumin
 Co-administration results in a risk of Warfarin over dose
 Rifampin (TB Antibiotic)
 CYP 34A inducer
 Reduces Tamoxifen’s
 Bioavailability by 86%
 Cmax by 55%
 Prozac (Anti-depressant)
 CYP 2D6 competitor
 Decreases the effect of Tamoxifen
http://alturl.com/apbr2
18

19. SPECIAL POPULATION STUDY
Brain cancer patients
New Indication
Treatment for malignant glioma
19

20. ABOUT THE POPULATION
 Rational for Special Population
 High level of cell proliferation in
brain
 Brain cells contain estrogen
receptors
 Proliferative signal transduction
in glioma cells has been shown to
occur through a predominantly
Protein Kinase C dependent
pathway
 P-glycoprotein functions as a
transporter in the blood-brain
barrier
20

21. PHARMACOKINETICS
Absorption
Oral absorption through the
portal vein into the liver
Excretion
Biliary system
Metabolism
First pass metabolism
CYP 450 enzymes
Distribution
Tissues expressing ER,
including the brain
ADME
21

22. PHARMACODYNAMICS
 Tamoxifen is an ER antagonist in the brain
 Prevents transcription
 Cell growth arrest/apoptosis
 Tamoxifen is the only PKC inhibitor small
enough to cross the blood-brain barrier
 Inhibits signal transduction
 Cell growth arrest/apoptosis
 Tamoxifen inhibits P-glycoprotein function
 Increased bioavailability of Tamoxifen
22

23. REFERENCES
 Avastin (bevacizumab) injection, solution [Genetech, Inc.]. US NLM, NIH, HHS.
Revised 01/2007.
<http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=53695&CFID=6856876
5&CFTOKEN=c7cde62162e43be5-8E980C43-A853-F363-
B83B961222D86D50&jsessionid=ca301da0de303c387869>
 Clinical Trials: Tamoxifen. US NLM, NIH, HHS.
<http://clinicaltrials.gov/ct2/results?term=tamoxifen>
 Fisher B., Costantino J.P., Wickerham D.L., Redmond C.K., Kavanah M., Cronin
W.M., Vogel V., Robidoux A., Dimitrov N., Atkins J., Daly M., Wieand S., Chiu E.T.,
Ford L., and Wolmark N. 1998. Tamoxifen for prevention of breast cancer: report
of the national surgical adjuvant breast and bowel project p-1 study. Journal of the
National Cancer Institute. 90 (18). 1371-1388
 Kleinsmith L.J., Kerrigan D., and Kelly J. 2010. Understanding cancer and related
topics: understanding esrogen receptors, tamoxifen, and raloxifene. National
Cancer Institute.
 The Merck Index. 13th Edition. Merck & Co., INC. Whitehouse Station, NJ. 2001.
23

24. REFERENCES
 Lien E.A., Solheim E., and Ueland P.M. 1991. Distribution of tamoxifen and its
metabolites in rat and human tissues during steady-state treatment. Cancer
Research. 51. 4837-4844
 Mackay H.J. and Twelves C.J. 2003. Protein kinase C: a target for anticancer
drugs.Endocrine-Related Cancer. 10. 389-396
 Fisher B., Costantino J.P., Wickerham D.L., Cecchini R.S., Cronin W.M., Robidoux A.,
Bevers T.B., Kavanah M.T., Atkins J.N., Margolese R.G., Runowicz C.D., James J.M.,
Ford L.G., and Wolmark N. 2005. Tamoxifen for the prevention of breast cancer:
current status of the national surgical adjuvant breast and bowel project P-1 study.
Journal of the National Cancer Institute. 97 (22). 1652-1662
 Nolvadex (tamoxifen citrate) Tablet [AstraZeneca Pharmaceuticals LP]. US NLM,
NIH, HHS. Revised 01/2007.
<http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=3420>
24

25. REFERENCES
 Schroth W., Goetz M.P., Hamann U., Fasching P.A., Schmidt M., Winter S., Fritz P.,
Simon W., Suman V.J., Ames M.M., Safgren S.L., Kuffel M.J., Ulmer H.U., Strick R.,
Beckmann M.W., Koelbl H., Weinshilboum R.M., Ingle J.N., Eichelbaum M., Schwab
M., and Brauch H. 2009. Association between CYP2D6 polymorphisms and
outcomes among women with early stage breast cancer treated with tamoxifen.
Journal of the American Medical Association. 302 (13). 1429-1436
 Ramachandran C., Khatib Z., Pefkarou A., Fort J., Fonseca H.B., Melnick S.J., and
Escalion E. 2004. Tamoxifen modulation of etoposide sytotoxicity involves inhibition
of protein kinase C activity and insulin-like growth factor II expression in brain tumor
cells. Journal of Neuro-Oncology. 67. 19-28
 Couldwell W.T., Hinton D.R., Surnock A.A., DeGiorgio C.M., Weiner L.P., Apuzzo M.L.J.,
Masri L., Law R.E., and Weiss M.H. 1996. Treatment of recurrent malignant gliomas
with chronic oral high-dose tamoxifen. Clinical Cancer Research. 2. 619-622
 Mandlekar S. and Kong A.N.T. 2001. Mechanisms of Tamoxifen – Induced
apoptosis. Apoptosis. 6. 469-477.
25

26. 26
26

27. 27