1) 10-069

J Breast Cancer 2010 December; 13(4): 325-36 R 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.

Source: http://www.ejbc.kr/Synapse/Data/PDFData/0096JBC/jbc-13-325.pdf

L.a., orange county gasoline prices lowest on labor day since 2010

L.A., Orange County Gasoline Prices Lowest on Labor Day Since 2010http://www.dailynews.com/general-news/20130902/la-orange-county-gas. Subscriber ServicesSubscribee-EditionMobileAlertsLocal AdsContact us L.A., Orange County Gasoline Prices Lowest on Labor Day Since 2010 LOS ANGELES (CNS) - The average price of a gallon of self-serve regular gasoline in Los Angeles Countyrose three-tenth

Structure-function relations of human hemoglobins

Structure-function relations of human hemoglobinshttp://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1484532 Note: Performing your original search, "hemoglobin koln" symptoms , in PubMed Central will retrieve 8 citations . Journal List > Proc (B ayl U niv M ed Cent) > v.19(3); Jul 2006Proc (Bayl Univ Med Cent). 2006 July; 19(3): 239–245. Copyright © 2

Copyright © 2010-2014 Internet pdf articles