Es ist nicht klar, wie groß die Rolle von Antibiotika https://antibiotika-wiki.de/ in den Wettbewerbsbeziehungen zwischen Mikroorganismen unter natürlichen Bedingungen ist. Zelman vaxman glaubte, dass diese Rolle minimal ist, Antibiotika werden nicht anders als in reinen Kulturen auf reichen Umgebungen gebildet. Anschließend wurde jedoch festgestellt, dass bei vielen Produzenten die Aktivität der antibiotikasynthese in Gegenwart anderer Arten oder spezifischer Produkte Ihres Stoffwechsels zunimmt.
1) 10-069
J Breast Cancer 2010 December; 13(4): 325-36R E V I E W A R T I C L E Use of Antidepressants in Patients with Breast Cancer Taking Tamoxifen Seong Hwan Kim, Mi-Ri Lee1, Keun-Cheol Lee2, Jin-Hwa Lee3, Hyuk-Chan Kwon4, Dae-Cheol Kim5, Kyeong Woo Lee6, Se-Heon Cho1
Departments of Psychiatry, 1Surgery, 2Plastic and Reconstructive Surgery, 3Radiology, 4Internal Medicine, 5Pathology, and6Rehabilitation Medicine, Dong-A University College of Medicine, Busan, Korea
Tamoxifen, a selective estrogen modulator has been used
sants to treat hot flashes or depression in patients with breast
for more than three decades to treat all stages of estrogen
cancer, may also alter enzyme activity and negatively affect
receptor (ER)-positive breast cancer and to prevent the
the outcomes of patients receiving adjuvant tamoxifen. This
disease. Tamoxifen is a pro-drug that requires metabolic
article reviews and discusses the following issues: tamoxifen
activation to 4-hydroxytamoxifen and 4-hydroxy-N-desmethyl-
metabolism, antiproliferative effects of tamoxifen and its
tamoxifen (endoxifen) to elicit its pharmacological activity.
metabolites, CYP2D6 genetic polymorphisms, treatment
Endoxifen has identical properties and potency with 4-
for hot flashes and depression in breast cancer, and the
hydroxytamoxifen, but is present in concentrations up to
pharmacological interactions between tamoxifen and anti-
10-fold higher than 4-hydroxytamoxifen. The cytochrome
depressants via CYP2D6. Although routine CYP2D6 testing
P450 2D6 (CYP2D6) enzyme plays a key role in converting
is not recommended yet, coadministration of potent or inter-
tamoxifen into its active metabolites with significantly greater
mediate CYP2D6 inhibitors in women taking tamoxifen
affinity for the ER and greater ability to inhibit cell proliferation.
Genetic variants in the CYP2D6 gene may result in CYP2D6enzymes with reduced or null activity, thereby decreasingthe anti-cancer effect. In addition to genetic inactivation of
Key Words: Antidepressants, Breast neoplasms, Cytochrome P450 2D6,
CYP2D6, inhibitors of CYP2D6, including some antidepres-
effective for patients with hormone receptor-positive
tumors. The standard endocrine treatment for premeno-
Breast cancer is the most common malignancy in
pausal women with ER-positive breast cancer is tamox-
women, and more than 1.5 million women are expected
ifen for 5 yr. In contrast, both tamoxifen and aromatase
to be newly diagnosed with the disease.(1) The occurrence
inhibitors (AIs) are acceptable treatment options for post-
of the disease in Korean women is rapidly increasing due
menopausal women.(3) But the use of AIs has been pro-
to a westernized lifestyle and early diagnosis.(2)
hibited in premenopausal patients with breast cancer,
The majority of the patients with breast cancer have
as it can activate ovarian functions and cause polycystic
tumors that express the estrogen receptor (ER) and/or
ovarian diseases.(4,5) Therefore, tamoxifen administration
progesterone receptor (PR) on the cell surfaces. Also,
is generally recommended as the principal treatment for
endocrine therapy, which reduces the estrogen level is
premenopausal hormone receptor-positive patients with
breast cancer or for patients in which AI use is inappro-
Department of Surgery, Dong-A University College of Medicine,3-1 Dongdaesin-dong, Seo-gu, Busan 602-715, Korea
Tamoxifen was approved by the US Food and Drug
Administration (FDA) in 1977 for use as an adjuvant in
E-mail: shcho1@dau.ac.kr Received: September 20, 2010 Accepted: October 15, 2010
the treatment of postmenopausal women with ER-positive
This paper was supported by Dong-A University Research Fund.
breast cancer or ductal carcinoma in situ and is currently
used in all stages of breast cancer.(6-8) As tamoxifen
depression in patients with cancer, they are also com-
has been widely used for the last 30 yr, it contributed to
monly prescribed as adjuvant therapy to treat neuropathic
reduce 50% of breast cancer recurrence and to decrease
pain and to relieve menopausal vasomotor symptoms such
the annual breast cancer death rate by one third. The
as hot flashes. The antiestrogen treatment can induce or
clinical effects of tamoxifen with respect to efficacy and
aggravate depression or anxiety, and commonly causes
toxicity vary widely among individuals. For example,
hot flashes, indicating that a discussion between the
30-40% of patients with ER-positive advanced breast
physicians treating breast cancer and the psychiatrist
cancer do not respond to tamoxifen, and all tumors that
may be required. Additionally the use of antidepressants
do respond eventually become resistant to tamoxifen
may act negatively on tamoxifen, from a pharmacolkinetic
treatment.(9) Genetic variability in the enzymes related
aspect, and influences the recurrence and survival rate
to tamoxifen metabolism is responsible for the failure
The present study aimed to review the use and effect
In Western countries, most patients with breast cancer
of antidepressants in patients with breast cancer, tamoxifen
are diagnosed after menopause, whereas 60% of the
metabolism, the effect of the cytochrome P450(CYP)2D6
patients are premenopausal women, and the mean age
polymorphism on tamoxifen function, and potential drug
of onset is 47.1 yr in Korea. The peak prevalence occurs
interactions between tamoxifen and antidepressants.
s, and the incidence progressively decreases
after menopause. Such a trend has been maintained
despite the increasing occurrence of breast cancer and
a westernized lifestyle.(10) Depression is the most common
psychiatric problems in patients with cancer. Its occur-
rence risk becomes higher when the onset age of breast
Many women experience distress following a diagnosis
cancer is low, so younger patients suffer more from psy-
of breast cancer, and some patients experience clinically
chiatric distress causing negative effects on their quality
significant depression.(16) The prevalence of depression
of life.(11) Because relatively younger populations are
in patients with breast cancer is estimated to be in the
diagnosed with breast cancer compared to Western coun-
range of 10-20%, depending on the method of assess-
tries, the prevalence of depression is high. The symptoms
ment. Rates appear higher in the first yr following diag-
of depression in patients with breast cancer not only have
nosis, especially in young women or in those treated with
of life, but also lower survival rate. Once the symptoms
Antidepressants are the most frequently prescribed
of depression and anxiety are severe, the patients’quality
medications in the world, and one-third of patients visiting
of life may be lowered, resulting in negative effects on the
medical offices in the United States are taking an anti-
progression and outcome of the disease.(12-14) Therefore,
depressant. Among the patients with breast cancer taking
treatment of depression is an important issue in patients
tamoxifen, 20-30% are also taking antidepressants.(18)
with breast cancer. But, as the treatment responses to
Currently, various classes of antidepressants are prescribed
antidepressants differ by gender and menopausal state,(15)
for the treatment of depression. Newer antidepressants,
different responses should be expected when treating
including selective serotonin reuptake inhibitors (SSRIs)
female patients with breast cancer than general patients
or serotonin norepinephrine reuptake inhibitors (SNRIs),
with depression, and a drug interaction must be con-
are the most commonly prescribed. Although, tricyclic
sidered if patients undergo chemotherapy or antiestrogen
antidepressants (TCAs) have been used effectively to
treat neuropathic pain in patients with cancer, their use
Although antidepressants are mainly used to relieve
for treating depression as a primary strategy has been
Antidepressants in Patients with Breast Cancer Taking Tamoxifen
largely limited. TCAs have a low therapeutic index, take
studies and open tests on the efficacy of antidepressants
longer to elucidate the clinical effects compared to the
for patients with cancer including breast cancer have been
newer antidepressants, and an overdose is can be highly
conducted, but the results have been equivocal. In the
fatal. The use of monoamine oxidase inhibitors extremely
largest 8-weeks trial, 549 patients including those with
difficult in patients with cancer, as they can cause a
breast cancer, pulmonary cancer, blood cancer, gyneco-
hypertensive crisis by taking sympathetic medications
logic cancer, and gastrointestinal cancer were randomly
concurrently or by eating foods containing tyramine.
assigned to receive either 20 mg of paroxetine daily or
Furthermore, coadministration with meperidine can
a placebo. In that study, Morrow et al.(23) reported the
cause hypertension, high fever, convulsions, and even
effectiveness of paroxetine for alleviating depressive
death. Therefore, the newer antidepressants such as
symptoms compared to the placebo group, but no differ-
the SSRIs or SNRIs are currently used as the first choice
ence was found in reducing fatigue between the groups.
medication in the treatment of depression or for meno-
In conclusion, pharmacologic studies on the effects of
pausal symptoms in patients with cancer.
antidepressants in patients with cancer and depression
So far, few clinical studies have been conducted on the
are limited due to the difficult current situation in con-
treatment of depression in patients with breast cancer.
ducting controlled pharmacologic trials, and, moreover,
Four double-blinded randomized controlled studies were
double-blinded studies of antidepressants in patients with
conducted only for patients with breast cancer; three
breast cancer are limited. Additionally, most of the studies
paroxetine studies and one mianserin study. Pezzella et
had limited numbers of test subjects, a short follow-up
al.(19) compared the effects and tolerability of paroxetine
period, and the data were assessed by different tools.
(20-40 mg/day) and amitriptyline (75-150 mg) in 179
Despite these limitations, the use of antidepressants in
patients with breast cancer and depression. After 8 weeks
patients with cancer is effective and similar to patients
of treatment, the depressive symptoms improved in 43.7%
with various other physical illnesses.
of the paroxetine group and 37.9% of the amitriptyline
group. Although both medications were effective for treat-
ing depression, the anticholinergic side effects occurred
Approximately 75% of menopausal women develop signs
at rates of 11.4% in the paroxetine group and 19.1% in the
of hot flashes. Typically, hot flashes begin with an abrupt
amitriptyline group. In the other double-blinded study,
flash in the chest, neck, and facial area, which tends to
the administration of paroxetine to 94 patients with breast
expand into other parts of the body, and is accompanied
cancer receiving chemotherapy was effective in improving
by skin rashes, perspiration, palpitation, anxiety, and
depression symptoms compared to the placebo.(20) But,
insomnia. In particular, hot flashes accompanied by the
in a double-blind, placebo-controlled study comparing
abrupt menopause after an ovariectomy, chemotherapy,
paroxetine (n=13), desipramine (n=11), or placebo (n=11)
or radiation therapy in patients with cancer are more
for 6 weeks, no significant treatment effect was found
frequent and intense compared to natural menopause.(24)
among the three groups.(21) The small number of women
Although the hot flash mechanism has not been clearly
in this study most likely contributed to the lack of a
elucidated, dysfunction of the body temperature control
statistical significance observed during the 6 weeks of
mechanism in the hypothalamus due to a reduction in
treatment. In a study evaluating the effect of mianserin
estrogen is considered to be the cause of the symptoms.(25)
including 55 patients with breast cancer without metas-
Changes in body temperature are recognized in the ther-
tasis, mianserin significantly improved depressive symp-
moregulatory center located in the medial preoptic area of
toms compared to the placebo group, and the treated
the hypothalamus, which controls physiological responses
group had a better dropout rate and side-effect frequency
that conserve or dissipate heat, such as skin vasodilata-
result than the placebo group.(22) Several double-blinded
tion or vasoconstriction. The threshold between sweating
and shivering (inter-threshold zone) is wide in premeno-
Among these antidepressants, paroxetine and velafaxine
pausal women, but narrow in menopausal women. An
are more effective for improving the frequency of hot
increase in body temperature precedes most hot flashes.
flashes in patients with breast cancer, and fluoxetine(38)
Because menopause is associated with a decline in estrogen
and setraline(39) are also effective for managing symptoms.
concentrations, and women with low amounts of circu-
Stearns et al.(34,40) reported the effect of paroxetine on
lating estrogens are more likely to have symptoms, estro-
reducing hot flash frequency and severity compared with
gen deprivation has been thought to be the most likely
a placebo in menopausal women and patients with breast
triggering event for hot flashes due to activation of the
cancer, respectively. In a good-quality trial that enrolled
heat loss mechanism by a small body temperature ele-
menopausal women, the paroxetine controlled release
groups (12.5 or 25 mg/day) experienced fewer daily hot
Although tamoxifen is generally well tolerated, up to
flashes than the placebo group (3.2-3.3 vs. 1.8, p=0.01)
80% of women who take tamoxifen complain of hot flashes
and reduced hot flash composite scores (frequency×sever-
and up to 45% of women grade the hot flashes as severe
ity, 62-65% vs. 38%, p=0.03).(34) In a fair-quality trial
enough to cause a decrease in quality of life and therapy
that included predominantly women with breast cancer
noncompliance.(27,28) To improve hot flash symptoms
using tamoxifen, the paroxeine groups (10 or 20 mg/day)
in healthy women, hormonal therapy such as estrogen
also showed fewer daily hot flash episodes compared with
has been used as the most common and effective treat-
placebo (50-51% vs. 16%, p<0.001) as well as a reduction
ment. Approximately 80-90% of patients administered
of composite score (54% vs. 19%, p<0.001) compared to
with hormonal medications report the desired effects.(29)
Exogenous estrogens are not commonly recommended
Velafaxine also showed excellent effects in several
for treating hot flashes in women with breast cancer,
studies for treating flushing including randomized con-
as they can cause recurrence and metastasis of breast
trolled trials. Loprinzi et al.(35) conducted a randomized
cancer.(30) Because of such a limitation, other therapies
double-blind, placebo-controlled study to assess the effi-
have been sought. Antidepressants including SSRIs and
cacy of venlafaxine in 221 patients with breast cancer,
SNRIs, clonidine and gabapentin are effective as nonhor-
69% of whom were taking tamoxifen. The subjects were
assigned to a placebo or one of three velafaxine groups
As estradiol (E2) works in the thermoregulatory center
(37.5, 70, or 150 mg daily) to compare the improvement
through serotonin,(32) antidepressants that act on the
of flushing after 4 weeks of treatment. The results showed
serotonin system have been tested as nonhormonal ther-
that the reduction in hot flash frequency was 19, 30, 46,
apy for hot flashes. Among the several serotonin recep-
and 58% and the decrease in composite scores was 27, 37,
tors, direct activation of the 5-HT2a receptor induces
61 and 61%, respectively. Although, all of the velafaxine
hyperthermia, and stimulation of the 5-HT1a receptor
groups showed a significant improvement compared to
results in hypothermia. So, a balance between the 5-HT1a
the placebo group, 70 mg velafaxine was the most effective
and 5-HT2a receptors might be important for optimizing
dose considering side effects. In another study evaluating
thermoregulation.(33) Because the development of flushing
the efficacy and tolerability of long-term treatment with
is related to a body temperature increase through an
venlafaxine for reducing vasomotor symptoms in patients
overload of the serotonin receptors in the hypothalamus,
with breast cancer, the use of the low dose venlafaxine
it has been suggested that SSRIs or SNRIs improve flush-
(37.5 mg/day) was associated with minimal side effects
ing.(34) In general, several studies have shown that these
and produced a good improvement in hot flashes.(41) Loibl
medications reduce hot flash frequency by about 60%,
et al.(42) compared the efficacy of clonidine (0.075 mg
compared with a decrease of 25-35% with a placebo.(31,
twice/day) and venlafaxine (37.5 mg twice/day) in a double-
blinded, randomized study. The investigators demonstrated
Antidepressants in Patients with Breast Cancer Taking Tamoxifen
that venlafaxine is significantly more effective in reducing
plasma tamoxifen concentrations revealed no statistically
the frequency of hot flashes in patients with breast cancer
significant differences in outcomes between women who
received 20 mg of tamoxifen daily and those who received
In conclusion, as both SSRIs and SNRIs have been
40 mg of tamoxifen daily, even though women in the 40
suggested as effective in reducing the vasomotor symp-
mg tamoxifen group had higher plasma tamoxifen concen-
toms of healthy menopausal women and female patients
trations than those in the 20 mg tamoxifen group.(46)
with breast cancer, regardless of whether they were
These results have been widely cited as evidence that
receiving endocrine treatment or not,(31,34-36) these
plasma tamoxifen concentration is not a predictor of
medications could be considered first line treatments to
improve menopausal symptoms in patients with breast
Tamoxifen undergoes extensive hepatic oxidation by
cancer or women in which hormonal therapy is not appro-
the cytochrome (CYP) P450 enzymes to several primary
priate. Therefore, SSRIs and SNRIs could be prescribed
and secondary metabolites with variable potencies toward
to treat hot flashes in patients with breast cancer, but
the ER. Major primary metabolites include N-desmethyl-
it would be safest to select a drug having a low possibility
tamoxifen, 4-hydroxytamoxifen, tamoxifen-N-oxide,
of drug interactions if patients are taking tamoxifen.
α-hydroxytamoxifen, and N-didesmethyltamoxifen.
N-desmethyltamoxifen, resulting from the CYP3A4/5-
mediated catalysis of tamoxifen, is the major primary
quantitative metabolite of tamoxifen and accounts for
approximately 92% of primary tamoxifen oxidation. N-
Tamoxifen has both estrogenic and antiestrogenic
desmethyltamoxifen has weak antiestrogenic effects
activity, depending on the target organ. These differ-
similar to tamoxifen.(48) Using N-desmethyltamoxifen
ential effects lead to clinical benefits as well as to side
as an intermediary substrate, it is biotransformed to α-
effects and, rarely, severe toxicity.(9) Tamoxifen is anti-
hydroxy-N-desmethyltamoxifen and N-didesmethyl-
estrogenic in the breast as well as in the brain, resulting
tamoxifen by CYP3A5 as well as 4-hydroxy-N-desmethyl-
in decreased breast cancer development and recurrence,
but leading to hot flashes. In contrast, tamoxifen is estro-
Jordan et al.(49,50) demonstrated that hepatic metab-
genic in the bone, liver, and uterus, resulting in improve-
olism of tamoxifen results in a statistically significant
ments in bone density and lipid profile, but also potentially
increase in its efficacy and they also showed, for the first
increasing the risk of both thromboembolic disease and
time, that 4-hydroxytamoxifen, one of the human tamox-
ifen metabolites is approximately 100 times more potent
The ER-dependent growth inhibitory effect of anti-
than tamoxifen as an estrogen antagonist. 4-hydroxy-
estrogens is mediated by activation of antiproliferative
tamoxifen possesses a much higher affinity for ERs and
transforming growth factor beta (TGFβ) signal trans-
is 30- to 100-fold more potent than tamoxifen in sup-
duction pathways.(43) TGFβis a strong inhibitor of breast
pressing estrogen-dependent cell proliferation.(51,52)
cancer cell growth and induces cell cycle arrest in the
For this reason, 4-hydroxytamoxifen has been considered
early G1 phase.(44) Although it is not clearly understood
as the major active metabolite of tamoxifen and is fre-
how tamoxifen causes depression or aggravates the illness,
quently used to characterize tamoxifen activity. In women
anti-manic effects of tamoxifen in bipolar disorder were
receiving tamoxifen at a dose of 20 mg/day, plasma steady
state concentrations of tamoxifen and N-desmethyltamo-
The mechanisms and effects of tamoxifen have been
xifen are 362.5 and 654.9 nM, respectively, whereas the
the subject of much scrutiny but remain obscure. Attempts
steady-state concentrations of 4-hydroxytamoxifen are
to link a clinical response to tamoxifen therapy with
extremely low (9 nM).(53) However, new data suggest
that endoxifen has identical properties and potency as
terization of tamoxifen metabolism demonstrated that
4-hydroxytamoxifen, but is present at higher blood con-
CYP3A is the major CYP isoform responsible for the for-
centrations than 4-hydroxytamoxifen.(54) Recent studies
mation of N-desmethyltamoxifen, whereas the genera-
have confirmed that endoxifen has equivalent potency
tion of endoxifen and 4-hydroxytamoxifen appear to be
to 4-hydroxytamoxifen in ER-αand ER-βbinding,(54)
catalyzed predominantly by CYP2D6. As the major meta-
in suppression of ER-dependent breast cancer prolifer-
bolites that determine the effects of tamoxifen are trans-
ation,(54,55) and in global ER-responsive gene expres-
formed by CYP2D6, the difference in the treatment res-
sion.(56) Because of such results, it is currently accepted
ponse could exist based on CYP2D6 enzyme activity.
that the major pharmacological effects of tamoxifen are
More than 100 CYP2D6 allelic variations have been
most largely affected by the blood concentration of endox-
identified,(58) and might explain, in part, the observed
interpatient variability in the concentrations of tamoxifen
Antiestrogen treatment of hormone responsive breast
and its metabolites. The frequency of the single nucleotide
cancer cells and breast cancer tissue results in enhanced
polymorphism in CYP2D6 varies according to race and
secretion of active TGFβ1; induction of TGFβ2-, and TGFβ
ethnicity.(59) Individuals can be divided into poor, inter-
type II receptor (TβRII)-expression; and subsequent
mediate, extensive, and ultra-rapid metabolizers based
activation of downstream TGFβsignal transduction path-
on the CYP2D6 genotype. An accepted classification of
ways. Blocking of TGFβsignal transduction leads to
CYP2D6 activity designates persons homozygous for alleles
antiestrogen resistance.(43) Buck et al.(57) investigated
that produce enzymes with normal activity (such as wild-
the breast cancer cell growth suppression effects of the
type CYP2D6*1) as extensive metabolizers (EM). Persons
six major metabolites including tamoxifen on the TGFβ
carrying multiple copies of CYP2D6 alleles associated with
signaling pathway and reported that only endoxifen and
high enzyme activity are termed ultra-rapid metabolizers
4-hydroxytamoxifen had significant antiproliferative
(UM), and individuals with one or two variant alleles with
activity and were able to induce TGFβ2 and TβRII. The
reduced or null activity are designated intermediate (IM)
authors suggested that TGFβ2 and TβRII are biological
and poor metabolizers (PM). While 60% of European indi-
indicators of tamoxifen treatment response in evaluating
viduals are homozygous for the active, most common
the tamoxifen treatment effect in breast cancer.
allele (CYP2D6*1), approximately 7% are homozygous for
The pharmacological action of tamoxifen is due to its
an inactive, variant allele (CYP2D6*4).(60) Approximately
conversion to active metabolites. Because there is strong
24% of African and African-American populations have
evidence that tamoxifen is converted to antiestrogenic
the CYP2D6*17 variant allele with reduced enzyme activ-
metabolites, which are more potent than tamoxifen itself,
ity,(61) and the most common allele in Asians (with an
altered patterns of tamoxifen metabolism might contribute
allele frequency >50%) is CYP2D6*10, which produces an
to interindividual variability in effects despite the same
enzyme with reduced activity (Table 1).(62)
dosage. For this reason, pharmacogenetic and drug inter-
It has been hypothesized that women have the CYP2D6
actions relating to CYP2D6 activity may affect endoxifen
enzyme with reduced activity, and that because this results
concentrations and possibly tamoxifen-associated long-
in presumably low endoxifen concentrations, these women
might have poor long-term treatment outcomes. The
North Central Cancer Treatment Group conducted a study
investigating the relationship between CYP2D6 genotypes
and treatment outcomes of tamoxifen with ER-positive
Multiple CYP isoenzymes including CYP3A, CYP2D6,
postmenopausal patients with breast cancer who were
CYP2C9, CYP2C19, CYP2B6, and CYP1A2 are involved
randomly assigned to receive 5 yr of tamoxifen.(63,64)
in tamoxifen metabolism. A comprehensive kinetic charac-
The investigators reported that the patients with the
Antidepressants in Patients with Breast Cancer Taking Tamoxifen
Table 1. Major CYP2D6 alleles, effect on enzyme metabolism, and allele frequencies in selected populations
CYP2D6 *4/*4 variant allele, absent of enzyme activity,
homozygous or heterozygous for CYP2D6*1 among pa-
had a significantly short relapse-free time and disease-
tients with ER-positive menopausal breast cancer.(69)
free survival compared to individuals with CYP2D6*4/wt
Some limitations exist when directly comparing these
or with the wt/wt genotype.(63) However, no difference
contradictory reports through a meta-analysis. First,
was found for the frequency of hot flashes by genotype.
most of the studies were conducted retrospectively and
A follow-up study by the same investigators reported
differences in genotype analysis methods, in tamoxifen
that not only the CYP2D6 variant allele, but also the
administration dose and administration period, and in the
concomitant prescription of CYP2D6 inhibitors was an
presence of comparison groups exist. In 2006, the FDA
independent predictor of poorer outcome in the same
Endocrinologic and Metabolic Drugs Advisory Committee
population.(64) Schroth et al.(65) assessed the predictive
discussed routine CYP2D6 genotyping for patients pre-
value of genetic variants of CYP2D6, CYP2C19, CYP2B6,
scribed tamoxifen, but no agreement was made.(70) Until
CYP2C9, and CYP3A5 for tamoxifen treatment outcome
now, no consistent established guideline exists as to
in 486 patients with breast cancer (206, tamoxifen treat-
whether the CYP2D6 genotype test must be conducted
ment group; 280, non-tamoxifen treatment group, mean
before using tamoxifen. Therefore, follow-up studies
follow-up investigation period of 71 months) and reported
must be conducted to support the necessity of CYP2D6
significantly more breast cancer recurrences, shorter
genotype testing in patients with breast cancer.
relapse-free periods and worse event-free survival rates
among patients carrying the *4, *5, *10, and *41 CYP2D6
alleles, compared with carriers of two functional alleles.
A follow-up large-scale study conducted over 6.3 yr
showed a significantly higher relapse risk in the IM and
Approximately 25% of all clinically used medications
PM than in the EM, and the relapse time in the PM was
are metabolized by CYP2D6, including antiarrhythmic
agents (propafenone, flecainide), beta-blockers (timolol,
Several retrospective studies have reported an inverse
metoprolol, alprenolol), antidepressants (tricyclic anti-
association between the CYP2D6 genotype and breast
depressants, fluoxetine, paroxetine, bupropion), anti-
cancer outcomes. Nowell et al.(67) reported better overall
psychotics, and opioids such as codeine, and dextro-
survival in tamoxifen-treated patients with breast cancer
metophan. Therefore, CYP2D6 genotype status may
and the CYP2D6*4 genotype. A Swedish study showed
influence the activity of many commonly used medications.
a 62% reduction of recurrence risk in women with at least
For example, PM may experience decreased analgesic
one CYP2D6*4 allele who were treated with tamoxifen.(68)
effect due to difficulty in converting codeine to morphine
In other retrospective large-scale studies performed by
the same investigators, patients homozygous for CYP2D6*4
UM could experience excessive effects. Use of CYP2D6
showed a better prognosis compared with those who were
inhibitors in patients who are being treated with tamox-
ifen, even if they have the homozygous active genotype,
up prospective study by the same investigators, women
could potentially affect breast cancer outcomes, in a
with homozygous or heterozygous for the variant CYP2D6
manner similar to PM. Inhibition of tamoxifen conversion
allele had a decreased endoxifen concentration, and, more-
to endoxifen may decrease the efficacy of tamoxifen
over, the coadministration of tamoxifen and CYP2D6
therapy and increase the risk of breast cancer development
inhibitors caused a reduction of endoxifen concentration
or recurrence. Medications that inhibit CYP2D6 may turn
in proportion to the potency of CYP2D6 inhibition.(53)
Borges et al.(73) conducted a prospective trial in 158 pati-
Women with breast cancer have high rates of depres-
ents with breast cancer who were taking tamoxifen to
sion and are likely to be prescribed antidepressants; there-
evaluate the effect of the CYP2D6 genotype and concomi-
fore, clarifying drug interactions between drugs to treat
tant medications on endoxifen plasma concentrations.
breast cancer and depression should become breast cancer
They found that the CYP2D6 genoptypes are highly asso-
research priorities. Several SSRIs and SNRIs are potent,
ciated with endoxifen plasma concentrations and account
moderate, or mild inhibitors of CYP2D6 (Table 2). Anti-
for their variability. While no significant differences in
depressants such as paroxetine, fluoxetine, and bupropion
mean plasma concentrations of tamoxifen, N-desmethyl-
strongly inhibit CYP2D6 enzyme activity, and sertaline,
tamoxifen, or 4-hydroxytamoxifen were observed between
duloxetine, and diphehydramine are graded as moderate
users and non-users of concomitant CYP2D6 inhibitors,
inhibitors. Consequently most antidepressants act as
the mean endoxifen plasma concentration was signifi-
CYP2D6 inhibitors and may increase the risk of breast
cantly lower in patients taking CYP2D6 inhibitors com-
cancer relapse or death.(71) Although consistent study
pared to that in patients who did not. When the authors
results are not available, most experts agree that caution
divided the CYP2D6 inhibitors into potent (paroxetine,
should be exercised when prescribing tamoxifen with a
fluoxetine) and weak (sertraline and citalopram), they
CYP2D6 inhibitor and consideration should be given to
found low serum concentrations of endoxifen in those
the use of an alternate antidepressant.
concomitantly treated with potent inhibitors of CYP2D6,
In an experiment conducted by the Consortium on Breast
and intermediate levels of endoxifen in those concomi-
Cancer Pharmacogenomics, coadministration of parox-
tantly treated with weak inhibitors. Concomitant use of
etine to women with wild-type CYP2D6 and on chronic
venlafaxine, which is considered the least potent inhibitor,
tamoxifen therapy was associated with a 56% reduction
showed no significant effect. The authors observed that
in plasma concentrations of endoxifen.(72) At the follow-
the mean plasma endoxifen concentration was signifi-
Table 2. Proposed risk of decreased metabolism of tamoxifen by antidepressants inhibiting the CYP2D6 enzyme
Consider use based on risk-benefit assessment
Consider use based on risk-benefit assessment
Consider use based on risk-benefit assessment
Consider use based on risk-benefit assessment
Antidepressants in Patients with Breast Cancer Taking Tamoxifen
cantly lower in CYP2D6 EM patients who were taking
the possibility of some reduction in the metabolism of
potent CYP2D6 inhibitors compared to that in patients
tamoxifen. It is suggested that venlafaxine has little or
who were not. Thus, CYP2D6 genotype and concomitant
no effect on the metabolism of tamoxifen and may be
potent CYP2D6 inhibitors are highly associated with
considered the safest choice of antidepressants. Moreover,
plasma endoxifen concentrations and may substantially
desvenlafaxine, the active metabolite of venlafaxine,
impact outcomes during tamoxifen treatment by pheno-
does not inhibit the activity of CYP2D6 even at twice
copying effects, i.e., converting an EM into a PM pheno-
the recommended therapeutic dose.(78-80) A clinical
trial investigating tamoxifen levels in women with breast
The influence of a concomitant CYP2D6 inhibitor on
cancer and in women at high risk for breast cancer who
tamoxifen-associated outcome has also been investi-
are receiving tamoxifen together with venlafaxine, citalo-
gated. Goetz et al.(64) demonstrated that women with
pram, escitalopram, sertraline, or gabapentin is currently
decreased CYP2D6 metabolism had increased rates of
ongoing and may help us develop guidelines about the
breast cancer recurrence and decreased relapse-free
risks associated with these medications when prescribed
survival time. The authors concluded that CYP2D6 inhi-
bitors should probably be avoided in patients being treated
with tamoxifen. Ahern et al.(74) investigated the associ-
ation between concurrent use of tamoxifen and CYP2D6
inhibiting medications and breast cancer recurrence
Tamoxifen has been used to treat and prevent breast
among Danish women diagnosed with early-stage, ER-
cancer for more than 30 yr. Tamoxifen itself is a relatively
positive breast cancer. They computed the breast cancer
weak selective estrogen receptor modulator and is con-
recurrence odds ratio (OR) and 95% confidence intervals
sidered a classical pro-drug, requiring metabolic activa-
for 15 medications including antidepressants and reported
tion to elicit pharmacological activity. CYP2D6 appears
that the pooled recurrence OR was null, and that recur-
to be the rate-limiting enzyme converting the pharmaco-
rence ORs for individual drugs ranged from 0.3 to 3.4.
logically inactive metabolites (tamoxifen and N-desmethyl-
The investigators suggested a null association between
tamoxifen) into endoxifen. Both genetic and environ-
drug-compromised CYP2D6 activity and breast cancer
mental (drug-induced) factors that alter CYP2D6 enzyme
recurrence among tamoxifen-treated women. However
activity affect tamoxifen treatment outcomes. In patients
that study had some limitations such as a small number
with breast cancer, antidepressants are commonly used
to treat symptoms of depression and anxiety or to alleviate
When reviewing the evidence from clinical and non-
menopausal symptom such as hot flashes. The use of
clinical studies regarding the effects of antidepressants
antidepressants in patients with cancer is effective and
on the CYP2D6 enzyme, there are consistent results that
safe, but most SSRIs or SNRIs are CYP2D6 inhibitors.
paroxetine,(21,53,71) fluoxetine,(21,53,71) and bupro-
Therefore, coadministration of potent or intermediate
pion(75,76) have a large effect on tamoxifen metabolism
CYP2D6 inhibitors in women taking tamoxifen should
and should not be used in women taking tamoxifen.
Currently, it is difficult to evaluate the clinical results
of antidepressants with mild and moderate inhibiting
potency; a retrospective study showed no association with
breast cancer recurrence and the use of citalopram.(77)
1. Anderson BO, Yip CH, Smith RA, Shyyan R, Sener SF, Eniu A, et
al. Guideline implementation for breast healthcare in low-income
However, when prescribing these antidepressants, it
and middle-income countries: overview of the Breast Health Global
should be considered a secondary option in which the
Initiative Global Summit 2007. Cancer 2008;113:2221-43.
risk of not treating depression needs to be weighed against
2. National Cancer Information Center. Annual Report of National Cancer
Registration. Goyang: National Cancer Center; 2007.
20. Roscoe JA, Morrow GR, Hickok JT, Mustian KM, Griggs JJ, Matteson
3. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects
SE, et al. Effect of paroxetine hydrochloride (Paxil) on fatigue and
of chemotherapy and hormonal therapy for early breast cancer on
depression in breast cancer patients receiving chemotherapy. Breast
recurrence and 15-year survival: an overview of the randomised trials.
21. Musselman DL, Somerset WI, Guo Y, Manatunga AK, Porter M,
4. Smith IE, Dowsett M. Aromatase inhibitors in breast cancer. N Engl
Penna S, et al. A double-blind, multicenter, parallel-group study of
paroxetine, desipramine, or placebo in breast cancer patients (stages
5. Mitwally MF, Casper RF. Use of an aromatase inhibitor for induction
I, II, III, and IV) with major depression. J Clin Psychiatry 2006;67:
of ovulation in patients with an inadequate response to clomiphene
citrate. Fertil Steril 2001;75:305-9.
22. van Heeringen K, Zivkov M. Pharmacological treatment of depres-
6. Cole MP, Jones CT, Todd ID. A new anti-oestrogenic agent in late
sion in cancer patients. A placebo-controlled study of mianserin. Br
breast cancer. An early clinical appraisal of ICI46474. Br J Cancer
23. Morrow GR, Hickok JT, Roscoe JA, Raubertas RF, Andrews PL,
7. Controlled trial of tamoxifen as adjuvant agent in management of early
Flynn PJ, et al. Differential effects of paroxetine on fatigue and
breast cancer. Interim analysis at four years by Nolvadex Adjuvant
depression: a randomized, double-blind trial from the University of
Trial Organisation. Lancet 1983;1:257-61.
Rochester Cancer Center Community Clinical Oncology Program. J
8. Fisher B, Costantino J, Redmond C, Poisson R, Bowman D, Couture
J, et al. A randomized clinical trial evaluating tamoxifen in the treat-
24. Carpenter JS, Andrykowski MA, Cordova M, Cunningham L, Studts
ment of patients with node-negative breast cancer who have estrogen-
J, McGrath P, et al. Hot flashes in postmenopausal women treated
receptor-positive tumors. N Engl J Med 1989;320:479-84.
for breast carcinoma: prevalence, severity, correlates, management,
9. Osborne CK. Tamoxifen in the treatment of breast cancer. N Engl J
and relation to quality of life. Cancer 1998;82:1682-91.
25. Freedman RR, Norton D, Woodward S, Cornelissen G. Core body
10. The Korean Breast Cancer Society. Nationwide Korean breast cancer
temperature and circadian rhythm of hot flashes in menopausal women.
data of 2002. J Korean Breast Cancer Soc 2004;7:72-83.
J Clin Endocrinol Metab 1995;80:2354-8.
11. Christensen S, Zachariae R, Jensen AB, Vaeth M, Moller S, Ravnsbaek
26. Freedman RR, Krell W. Reduced thermoregulatory null zone in post-
J, et al. Prevalence and risk of depressive symptoms 3-4 months post-
menopausal women with hot flashes. Am J Obstet Gynecol 1999;181:
surgery in a nationwide cohort study of Danish women treated for
early stage breast-cancer. Breast Cancer Res Treat 2009;113:339-55.
27. Goetz MP, Loprinzi CL. A hot flash on tamoxifen metabolism. J
12. So WK, Marsh G, Ling WM, Leung FY, Lo JC, Yeung M, et al.
Anxiety, depression and quality of life among Chinese breast cancer
28. Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah
patients during adjuvant therapy. Eur J Oncol Nurs 2010;14:17-22.
M, Cronin WM, et al. Tamoxifen for prevention of breast cancer:
13. Andritsch E, Dietmaier G, Hofmann G, Zloklikovits S, Samonigg
report of the National Surgical Adjuvant Breast and Bowel Project
H. Global quality of life and its potential predictors in breast cancer
P-1 Study. J Natl Cancer Inst 1998;90:1371-88.
patients: an exploratory study. Support Care Cancer 2007;15:21-30.
29. Notelovitz M, Lenihan JP, McDermott M, Kerber IJ, Nanavati N,
14. Shapiro SL, Lopez AM, Schwartz GE, Bootzin R, Figueredo AJ,
Arce J. Initial 17beta-estradiol dose for treating vasomotor symptoms.
Braden CJ, et al. Quality of life and breast cancer: relationship to
psychosocial variables. J Clin Psychol 2001;57:501-19.
30. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg
15. Thase ME, Entsuah R, Cantillon M, Kornstein SG. Relative antide-
C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin
pressant efficacy of venlafaxine and SSRIs: sex-age interactions. J
in healthy postmenopausal women: principal results From the Women’s
Womens Health (Larchmt) 2005;14:609-16.
Health Initiative randomized controlled trial. JAMA 2002;288:321-33.
16. Payne DK, Hoffman RG, Theodoulou M, Dosik M, Massie MJ.
31. Nelson HD, Vesco KK, Haney E, Fu R, Nedrow A, Miller J, et al.
Screening for anxiety and depression in women with breast cancer.
Nonhormonal therapies for menopausal hot flashes: systematic review
Psychiatry and medical oncology gear up for managed care. Psycho-
and meta-analysis. JAMA 2006;295:2057-71.
32. Sumner BE, Grant KE, Rosie R, Hegele-Hartung C, Fritzemeier KH,
17. Fann JR, Thomas-Rich AM, Katon WJ, Cowley D, Pepping M,
Fink G. Effects of tamoxifen on serotonin transporter and 5-hydro-
McGregor BA, et al. Major depression after breast cancer: a review of
xytryptamine(2A) receptor binding sites and mRNA levels in the brain
epidemiology and treatment. Gen Hosp Psychiatry 2008;30:112-26.
of ovariectomized rats with or without acute estradiol replacement.
18. Consortium on Breast Cancer Pharmacogenomics. Drug-interactions
Brain Res Mol Brain Res 1999;73:119-28.
with Tamoxifen: a Guide for Breast Cancer Patients and Physician.
33. Stearns V, Ullmer L, Lopez JF, Smith Y, Isaacs C, Hayes D. Hot
Indianapolis: Indiana University School of Medicine; 2008.
19. Pezzella G, Moslinger-Gehmayr R, Contu A. Treatment of depression
34. Stearns V, Beebe KL, Iyengar M, Dube E. Paroxetine controlled release
in patients with breast cancer: a comparison between paroxetine and
in the treatment of menopausal hot flashes: a randomized controlled
amitriptyline. Breast Cancer Res Treat 2001;70:1-10.
Antidepressants in Patients with Breast Cancer Taking Tamoxifen
35. Loprinzi CL, Kugler JW, Sloan JA, Mailliard JA, LaVasseur BI,
fication, pharmacology, and significance. Breast Cancer Res Treat
Barton DL, et al. Venlafaxine in management of hot flashes in sur-
vivors of breast cancer: a randomised controlled trial. Lancet 2000;356:
51. Borgna JL, Rochefort H. Hydroxylated metabolites of tamoxifen are
formed in vivo and bound to estrogen receptor in target tissues. J
36. Loprinzi CL, Diekmann B, Novotny PJ, Stearns V, Sloan JA. Newer
antidepressants and gabapentin for hot flashes: a discussion of trial
52. Robertson DW, Katzenellenbogen JA, Long DJ, Rorke EA, Katze-
nellenbogen BS. Tamoxifen antiestrogens. A comparison of the
37. Stearns V. Clinical update: new treatments for hot flushes. Lancet
activity, pharmacokinetics, and metabolic activation of the cis and
trans isomers of tamoxifen. J Steroid Biochem 1982;16:1-13.
38. Loprinzi CL, Sloan JA, Perez EA, Quella SK, Stella PJ, Mailliard
53. Jin Y, Desta Z, Stearns V, Ward B, Ho H, Lee KH, et al. CYP2D6
JA, et al. Phase III evaluation of fluoxetine for treatment of hot flashes.
genotype, antidepressant use, and tamoxifen metabolism during
adjuvant breast cancer treatment. J Natl Cancer Inst 2005;97:30-9.
39. Kimmick GG, Lovato J, McQuellon R, Robinson E, Muss HB. Ran-
54. Johnson MD, Zuo H, Lee KH, Trebley JP, Rae JM, Weatherman RV,
domized, double-blind, placebo-controlled, crossover study of ser-
et al. Pharmacological characterization of 4-hydroxy-N-desmethyl
traline (Zoloft) for the treatment of hot flashes in women with early
tamoxifen, a novel active metabolite of tamoxifen. Breast Cancer
stage breast cancer taking tamoxifen. Breast J 2006;12:114-22.
40. Stearns V, Slack R, Greep N, Henry-Tilman R, Osborne M, Bunnell
55. Lim YC, Desta Z, Flockhart DA, Skaar TC. Endoxifen (4-hydroxy-
C, et al. Paroxetine is an effective treatment for hot flashes: results
N-desmethyl-tamoxifen) has anti-estrogenic effects in breast cancer
from a prospective randomized clinical trial. J Clin Oncol 2005;23:
cells with potency similar to 4-hydroxy-tamoxifen. Cancer Chemother
41. Biglia N, Torta R, Roagna R, Maggiorotto F, Cacciari F, Ponzone
56. Lim YC, Li L, Desta Z, Zhao Q, Rae JM, Flockhart DA, et al. Endo-
R, et al. Evaluation of low-dose venlafaxine hydrochloride for the
xifen, a secondary metabolite of tamoxifen, and 4-OH-tamoxifen
therapy of hot flushes in breast cancer survivors. Maturitas 2005;52:
induce similar changes in global gene expression patterns in MCF-7
breast cancer cells. J Pharmacol Exp Ther 2006;318:503-12.
42. Loibl S, Schwedler K, von Minckwitz G, Strohmeier R, Mehta KM,
57. Buck MB, Coller JK, Murdter TE, Eichelbaum M, Knabbe C. TGF-
Kaufmann M. Venlafaxine is superior to clonidine as treatment of
beta2 and TbetaRII are valid molecular biomarkers for the antipro-
hot flashes in breast cancer patients--a double-blind, randomized
liferative effects of tamoxifen and tamoxifen metabolites in breast
cancer cells. Breast Cancer Res Treat 2008;107:15-24.
43. Knabbe C, Kopp A, Hilgers W, Lang D, Muller V, Zugmaier G, et
58. Hiratsuka M, Agatsuma Y, Omori F, Narahara K, Inoue T, Kishikawa
al. Regulation and role of TGF beta production in breast cancer. Ann
Y, et al. High throughput detection of drug-metabolizing enzyme
polymorphisms by allele-specific fluorogenic 5’ nuclease chain reac-
44. Zugmaier G, Ennis BW, Deschauer B, Katz D, Knabbe C, Wilding G,
tion assay. Biol Pharm Bull 2000;23:1131-5.
et al. Transforming growth factors type beta 1 and beta 2 are equipo-
59. Hiratsuka M, Takekuma Y, Endo N, Narahara K, Hamdy SI, Kishikawa
tent growth inhibitors of human breast cancer cell lines. J Cell Physiol
Y, et al. Allele and genotype frequencies of CYP2B6 and CYP3A5
in the Japanese population. Eur J Clin Pharmacol 2002;58:417-21.
45. Yildiz A, Guleryuz S, Ankerst DP, Ongur D, Renshaw PF. Protein
60. Nasu K, Kubota T, Ishizaki T. Genetic analysis of CYP2C9 polymor-
kinase C inhibition in the treatment of mania: a double-blind, placebo-
phism in a Japanese population. Pharmacogenetics 1997;7:405-9.
controlled trial of tamoxifen. Arch Gen Psychiatry 2008;65:255-63.
61. Coughtrie MW, Gilissen RA, Shek B, Strange RC, Fryer AA, Jones
46. Bratherton DG, Brown CH, Buchanan R, Hall V, Kingsley Pillers
PW, et al. Phenol sulphotransferase SULT1A1 polymorphism: mol-
EM, Wheeler TK, et al. A comparison of two doses of tamoxifen
ecular diagnosis and allele frequencies in Caucasian and African
(Nolvadex) in postmenopausal women with advanced breast cancer:
populations. Biochem J 1999;337:45-9.
10 mg bd versus 20 mg bd. Br J Cancer 1984;50:199-205.
62. Hollander M, Wolfe D. Nonparametric Statistical Methods. New
47. Decensi A, Gandini S, Guerrieri-Gonzaga A, Johansson H, Manetti
L, Bonanni B, et al. Effect of blood tamoxifen concentrations on
63. Goetz MP, Rae JM, Suman VJ, Safgren SL, Ames MM, Visscher DW,
surrogate biomarkers in a trial of dose reduction in healthy women.
et al. Pharmacogenetics of tamoxifen biotransformation is associated
with clinical outcomes of efficacy and hot flashes. J Clin Oncol 2005;
48. Clarke R, Liu MC, Bouker KB, Gu Z, Lee RY, Zhu Y, et al. Anties-
trogen resistance in breast cancer and the role of estrogen receptor
64. Goetz MP, Knox SK, Suman VJ, Rae JM, Safgren SL, Ames MM,
signaling. Oncogene 2003;22:7316-39.
et al. The impact of cytochrome P450 2D6 metabolism in women
49. Jordan VC, Collins MM, Rowsby L, Prestwich G. A monohydroxy-
receiving adjuvant tamoxifen. Breast Cancer Res Treat 2007;101:
lated metabolite of tamoxifen with potent antioestrogenic activity. J
65. Schroth W, Antoniadou L, Fritz P, Schwab M, Muerdter T, Zanger
50. Jordan VC. Metabolites of tamoxifen in animals and man: identi-
UM, et al. Breast cancer treatment outcome with adjuvant tamoxifen
relative to patient CYP2D6 and CYP2C19 genotypes. J Clin Oncol
No increase in breast cancer recurrence with concurrent use of tamo-
xifen and some CYP2D6-inhibiting medications. Cancer Epidemiol
66. Schroth W, Goetz MP, Hamann U, Fasching PA, Schmidt M, Winter
S, et al. Association between CYP2D6 polymorphisms and outcomes
75. Kotlyar M, Brauer LH, Tracy TS, Hatsukami DK, Harris J, Bronars
among women with early stage breast cancer treated with tamoxifen.
CA, et al. Inhibition of CYP2D6 activity by bupropion. J Clin Psy-
67. Nowell SA, Ahn J, Rae JM, Scheys JO, Trovato A, Sweeney C, et al.
76. Reese MJ, Wurm RM, Muir KT, Generaux GT, St John-Williams
Association of genetic variation in tamoxifen-metabolizing enzymes
L, McConn DJ. An in vitro mechanistic study to elucidate the desi-
with overall survival and recurrence of disease in breast cancer pati-
pramine/bupropion clinical drug-drug interaction. Drug Metab Dispos
ents. Breast Cancer Res Treat 2005;91:249-58.
68. Wegman P, Vainikka L, Stal O, Nordenskjold B, Skoog L, Rutqvist
77. Hernandez RK, Sorensen HT, Jacobsen J, Pedersen L, Lash TL.
LE, et al. Genotype of metabolic enzymes and the benefit of tamo-
Tamoxifen treatment in Danish breast cancer patients and 5-year
xifen in postmenopausal breast cancer patients. Breast Cancer Res
risk of arterial atherosclerotic events: a null association. Cancer Epi-
demiol Biomarkers Prev 2008;17:2509-11.
69. Wegman P, Elingarami S, Carstensen J, Stal O, Nordenskjold B,
78. Patroneva A, Connolly SM, Fatato P, Pedersen R, Jiang Q, Paul J, et
Wingren S. Genetic variants of CYP3A5, CYP2D6, SULT1A1,
al. An assessment of drug-drug interactions: the effect of desven-
UGT2B15 and tamoxifen response in postmenopausal patients with
lafaxine and duloxetine on the pharmacokinetics of the CYP2D6
breast cancer. Breast Cancer Res 2007;9:R7.
probe desipramine in healthy subjects. Drug Metab Dispos 2008;
70. CYP2D6 pharmacogenomics of tamoxifen treatment. Technol Eval
Cent Asses Program Exec Summ 2008;23:1-4.
79. Nichols AI, Fatato P, Shenouda M, Paul J, Isler JA, Pedersen RD, et
71. Goetz MP, Kamal A, Ames MM. Tamoxifen pharmacogenomics:
al. The effects of desvenlafaxine and paroxetine on the pharmaco-
the role of CYP2D6 as a predictor of drug response. Clin Pharmacol
kinetics of the cytochrome P450 2D6 substrate desipramine in healthy
adults. J Clin Pharmacol 2009;49:219-28.
72. Stearns V, Johnson MD, Rae JM, Morocho A, Novielli A, Bhargava
80. Preskorn SH, Nichols AI, Paul J, Patroneva AL, Helzner EC, Guico-
P, et al. Active tamoxifen metabolite plasma concentrations after
Pabia CJ. Effect of desvenlafaxine on the cytochrome P450 2D6
coadministration of tamoxifen and the selective serotonin reuptake
enzyme system. J Psychiatr Pract 2008;14:368-78.
inhibitor paroxetine. J Natl Cancer Inst 2003;95:1758-64.
81. Tamoxifen in Women With Breast Cancer and in Women at High-
73. Borges S, Desta Z, Li L, Skaar TC, Ward BA, Nguyen A, et al. Quan-
Risk of Breast Cancer Who Are Receiving Venlafaxine, Citalopram,
titative effect of CYP2D6 genotype and inhibitors on tamoxifen
Escitalopram, Gabapentin, or Sertraline. U.S National Institutes of
metabolism: implication for optimization of breast cancer treatment.
Health. http://www.clinicaltrials.gov/ct2/show/NCt00667121?term=
endoxifen+levels+AND+antidepressnats&rank=1. Accessed August
74. Ahern TP, Pedersen L, Cronin-Fenton DP, Sorensen HT, Lash TL.
BARR’S SMART MOVE IN THE ENHANCED WATER MARKET WITH THE RE-LAUNCH OF VITSMART Following Barr’s acquisition of the Vitsmart enhanced water brand in January this year, the company will completely re-launch the brand with a new formulation, a new vitamin mix and a range of 5 exciting new flavours in new unique shaped 500ml bottles from November 2008. The Vitsmart brand started the enhan
Introduction Diane P. Freedman Martha Stoddard Holmes That our world increasingly concerns the body should come as no surprise. Inthe United States, at least, we see television advertisements probably once con-sidered in bad taste for products we are now willing to admit or think we need:Depends undergarments or Detrol pills for incontinence, Viagra for erectiledysfunction, SSRIs for