The Toxicology of Tamoxifen

Louise Roy
November 14, 2007
Agenda
• Tamoxifen
• Pathophysiology
• Physico-chemical properties
• Toxicokinetics
– Absorption, distribution, metabolism, elimination

• Tamoxifen: Risks
• Research
Tamoxifen:
• Non-steroidal agent with potent
antiestrogenic properties.
• Potent anticancer agent known to interrupt
estrogen activity of malignant mammary
gland cells for the treatment of advanced
and early breast cancer.
• FDA and Health Canada approval.
Tamoxifen: (2)
• Endocrine treatment of choice, 5 year regime of
20 mg of tamoxifen per day.
• Study known as the Breast Cancer Prevention
Trial (BCPT) indicates that tamoxifen reduced
breast cancer risk by one-half:
– 49% reduction in incidence of invasive breast cancer.
– 50% reduction in incidence of non-invasive breast
cancer.

• Conclusive evidence that tamoxifen reduces

the risk for contralateral breast cancer by 47%.
Pathophysiology:

• Selective estrogen receptor modulator

compete with estradiol for estrogen
receptor protein binding in cytosols
derived from human breast
adenocarcinomas.
Physico-chemical properties
• Synthetic anti-estrogen substance.
• (Z)-2-[4-(1,2-Diphenylbut-1-enyl)phenony]-N, N-
dimethylethylamine.
• C26H29NO
• N-desmethyl and 4-Hydroxytamoxifen are the major
metabolites.
• Molecular weight: 563.6 g/mol.
• pKa= 8.85 (Dissociation constants).
• Sensitive to UV light.
Tamoxifen molecule:
Absorption:

• Route of entry: oral absorption.

• Rate of absorption : Peak serum concentrations
occur 3-6 h after drug intake.
• Steady-state plasma concentrations of
tamoxifen following continuous oral
administration of 10 mg twice daily for 3 months
average 120 ng/mL (range: 67-183 ng/mL).
Distribution:
• Tamoxifen is more than 99% protein-
bound.
• Albumin is the predominant carrier in
human plasma.
• Distribution half-life is 7-14 hours.
• Volume of distribution is 50-60l/kg.
Distribution: (2)
• Concentration of tamoxifen and its metabolites
in pleural, pericardial and peritoneal effusions
equal those detected in serum (effusion/serum
ratio is 0.2 to 1).
• Trace amounts have been detected in
cerebrospinal fluid. (CSF/serum ratio less than
0.02).
• Distribution of tamoxifen in the cytosol of
human breast tumor tissue appears to parallel
the relative concentrations present in serum.
Metabolism:

• Tamoxifen is metabolized in the liver, principally

by demethylation and to a small degree by
subsequent deamination and also by
hydroxylation.
• Data from animal studies suggest that
tamoxifen and /or its metabolites undergo
extensive enterohepatic circulation.
Metabolism: (2)

• Tamoxifen is a substrate of cytochrome P450

enzymes CYP3A, CYP2C9 and CYP2D6 and
an inhibitor of CYP2C8.
• Antidepressants (Paxil, Prozac etc.) can
decrease the effectiveness of tamoxifen
because these drugs compete for the CYP2D6
enzyme which is needed to metabolize
tamoxifen into the active form endoxifen.
Excretion:
• Primary route of excretion is biliary and fecal
(slowly excreted in over a 2 week period),
mostly as polar conjugates. Secondary route of
excretion is renal, less than 1% is excreted in
the urine.
• The elimination half-life of tamoxifen is about 5-
7 days and the elimination half-life of the major
metabolite is estimated to be 7-14 days.
(biphasic).
• All metabolites showed first-order elimination
curves.
Tamoxifen: Risks
• Animal data: Estrogenic agonist effects become
manifest at dosages equivalent to 10-100 times
the human therapeutic dose.
• Values for the oral LD50 in mice range from 3-6 g
kg -1 and in rats from 1.2-2.5 g kg -1.
• One study on humans to determine the
maximum tolerated dose (loading doses 400
mg/sq m with maintenance dosages of 150
mg/sq m given twice daily) generated an acute
neurotoxicity.
Carcinogenicity: Risks

• Carcinogenic to humans, classified by IARC

(1996) as a group 1.
– Sufficient evidence in humans for the carcinogenicity
of tamoxifen in increasing the risk for endometrial
cancer.
– Inadequate evidence in humans for the
carcinogenicity of tamoxifen in other organs.

• Well-recognized rat hepatocarcinogen.

Tamoxifen: Risks (2)

• According to the BCPT results, the risk ratio

are:
– Uterine cancer (RR=2.53).
– Thromboembolic:
• Deep vein thrombosis (RR=1.60).
• Pulmonary embolism (RR=3.01).
• Cerebral vascular accident (RR=1.59).
– Cataract (RR=1.14)
Genotoxicity: Risks
• In vitro data: Results of limited in vitro studies on
the effects of tamoxifen suggest that tamoxifen
induces cell death through an apoptotic pathway.
Tamoxifen was found to be cytostatic or cytotoxic,
and caused morphological changes and DNA
degradation (in two non-breast cancer cell lines-
human cervical carcinoma cells and murine
erythroleukemic cells- at different concentrations
and exposure duration). (Majumdar & al.)
• Tamoxifen can be genotoxic (DNA-damaging
potential) for normal and cancer cells by free
radicals generation. (Wozniak & al.)
Reproductive: Risks

• Tamoxifen is FDA pregnancy risk

category D (positive evidence of risk)-
Studies in pregnant women have
demonstrated a risk to the fetus.
• It is not known if tamoxifen is distributed
trough mother’s milk.
Tamoxifen: Risks
• In human tamoxifen might cause hepatotoxicity.
• Side effects (2.5-5%): nausea, vomiting, hot
flashes, headache, hypercalcemia, menstrual
disturbance,endometrial polyps, thickened
endometria, fluid retention, dizziness, skin rash,
pain of the calf, chest pain or shortness of
breath, symptoms of stroke (weakness,
difficulty walking or talking or numbness), hair
loss.
Diagnostic tests

• Testing is aimed at end organs effects:

– Bone marrow, liver, hypercalcemia.

• CBC and electrolytes.

• Serum calcium.
• Specific levels of tamoxifen are not used
to guide management.
Research: new drug
• Raloxifene or new drugs may be more
effective second generation successors
with weaker estrogen agonist effects on
the uterus.
• Much shorter clinical use.
• Long-term side effects still need to be
carefully monitored.
Research (2)

• Research studies have demonstrated that

BAG-1 (multifunctional protein) is an important
molecule in breast cancer, potentially
modulating both cell survival and response to
nuclear hormones such as estrogens. The
development of new agents to interfere with
BAG-1 functions is considered among new
developments breast cancer research.
Research (3)

• Molecular targets of breast cancer

therapy research should be pursued to
determine the amounts of drugs below
the dose range in which benefits are
compromised by toxic side effects, which
is different than the highest dose still
tolerated by the patient.
References

• Yao, A. (2007). New developments in breast cancer research.

Horizons in cancer research, 23, 161.
• Mehreen, L. & Khanam A. (2005). Evaluation of toxicities
induced by chemotherapy in breast cancer patients.
Biomedicine & Pharmacotherapy, 59, 524-527.
• White, I.N.H. (2003). Tamoxifen: Is it safe? Comparison of
activation and detoxication mechanisms in rodents and in
humans. Current drug metabolism, 4, 223-239.
• Furr B. J. A., & Jordan, V. C. (1984). The pharmacology and
clinical uses of Tamoxifen. Pharmac. Ther., 25, 127-205.
References (2)

• Majumdar, S. K. a. a. (2001). In vitro investigations on the

toxicity and cell death induced by tamoxifen on two non-breast
cancer cell types. Journal of Biomedicine and Biotechnology.,
1(3), 99-107.
• Dart, R. C. et al. (2004). Medical toxicology. (Third ed.).
Philadelphia: Lippincott Williams & Wilkins.
• Smedira, H. J. (2000). Practical issues in counseling healthy
women about their breast cancer risk women about their
breast cancer risk and use of tamoxifen citrate. Arch Intern
Med. , 160(Nov.), 3034-3042.
References (3)

• Bostrom, A., & et al. (1999). Radiation recall-Another

call with Tamoxifen. Acta Oncologia., 38(7), 955-959
• Tamoxifen citrate
http://www.inchem.org/documents/pims/pharm/tamoxife.
htm
• http://toxnet.nlm.nih.gov/cgi-bin/sis/search
• Wozniak, K., & et al. (2007). The DNA-damaging
potential of tamoxifen in breast cancer and normal cells.
Arch.Toxicol., 81, 519-527.