View source for Tamoxifen

{{Short description|Selective estrogen receptor modulator}}
{{Use dmy dates|date=February 2025}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Drugbox
| Watchedfields = changed
| verifiedrevid = 470477095
| image = Tamoxifen2DACS.svg
| image_class = skin-invert-image
| width = 250
| alt =
| image2 = Tamoxifen-3D-balls.png
| width2 = 175
| alt2 =

<!-- Clinical data -->
| tradename = Nolvadex, others<ref name="drug dictionary">{{Cite web |date=2 February 2011 |title=NCI Drug Dictionary |url=https://www.cancer.gov/publications/dictionaries/cancer-drug/def/tamoxifen-citrate |url-status=live |archive-url=https://web.archive.org/web/20151208154459/http://www.cancer.gov/publications/dictionaries/cancer-drug?CdrID=42901 |archive-date=8 December 2015 |access-date=12 September 2021}}</ref>
| Drugs.com = {{drugs.com|monograph|tamoxifen-citrate}}
| MedlinePlus = a682414
| DailyMedID = Tamoxifen
| pregnancy_AU = B3
| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{Cite web |date=25 July 2019 |title=Tamoxifen Use During Pregnancy |url=https://www.drugs.com/pregnancy/tamoxifen.html |access-date=27 January 2020 |website=Drugs.com}}</ref>
| pregnancy_category=
| routes_of_administration = [[Oral administration|By mouth]]
| class = [[Selective estrogen receptor modulator]]
| ATC_prefix = L02
| ATC_suffix = BA01

<!-- Legal status -->
| legal_AU = S4
| legal_AU_comment  =
| legal_BR          = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->
| legal_BR_comment  =
| legal_CA = Rx-only
| legal_CA_comment  = <ref>{{cite web | title=Nolvadex Product information | website=[[Health Canada]] | date=1 April 2003 | url=https://health-products.canada.ca/dpd-bdpp/info?lang=eng&code=16822 | access-date=17 February 2025}}</ref><ref>{{cite web | title=Nolvadex-D Product information | website=[[Health Canada]] | date=22 March 2023 | url=https://health-products.canada.ca/dpd-bdpp/info?lang=eng&code=18639 | access-date=17 February 2025}}</ref>
| legal_DE          = <!-- Anlage I, II, III or Unscheduled -->
| legal_DE_comment  =
| legal_NZ          = <!-- Class A, B, C -->
| legal_NZ_comment  =
| legal_UK = POM
| legal_UK_comment  =
| legal_US = Rx-only
| legal_US_comment = <ref>{{Cite web |title=Tamoxifen citrate tablet, film coated |url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c82205a3-ae0c-4ce5-b04b-9581cd8c70d4 |access-date=12 September 2021 |website=DailyMed}}</ref><ref>{{Cite web |title=Soltamox- tamoxifen citrate liquid |url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1e6ff055-590c-41e6-9530-1fdf04cdbd02 |access-date=12 September 2021 |website=DailyMed}}</ref>
| legal_EU          =
| legal_EU_comment  =
| legal_UN          = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment  =
| legal_status      = <!-- For countries not listed above -->

<!-- Pharmacokinetic data -->
| bioavailability = ~100%<ref name="MorelloWurz2003" /><ref name="BrennerStevens2017" />
| protein_bound = >99% ([[human serum albumin|albumin]])<ref name="MorelloWurz2003" /><ref name="ChabnerLongo2011" />
| metabolism = [[Liver]] ([[CYP3A4]], [[CYP2C9]], [[CYP2D6]])<ref name="MorelloWurz2003" /><ref name="Nolvadex-Label">{{Cite web |date=3 November 2016 |title=Nolvadex (Tamoxifen Citrate) tablets |url=https://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=234988 |access-date=12 September 2021 |website=DailyMed}}</ref><ref name="Sanchez-SpitmanSwen2019" />
| metabolites = • [[N-Desmethyltamoxifen|''N''-Desmethyltamoxifen]]<ref name="Sanchez-SpitmanSwen2019" /><ref name="pmid23962908" /><br />• [[Endoxifen]] (4-hydroxy-''N''-desmethyltamoxifen)<ref name="Sanchez-SpitmanSwen2019" /><ref name="pmid23962908" /><br />• [[Afimoxifene]] (4-hydroxytamoxifen)<ref name="Sanchez-SpitmanSwen2019" /><ref name="pmid23962908" /><br />• [[N,N-Didesmethyltamoxifen|''N'',''N''-Didesmethyltamoxifen]]<ref name="Sanchez-SpitmanSwen2019" /><br />• [[Norendoxifen]] (4-hydroxy-''N'',''N''-didesmethyltamoxifen)<ref name="Sanchez-SpitmanSwen2019" /><br />• Others, [[conjugation (biochemistry)|conjugates]]<ref name="Sanchez-SpitmanSwen2019" /><ref name="pmid21451508" /><ref name="Nagar2010" />
| onset             =
| elimination_half-life = 5–7 days<ref name="MorelloWurz2003" /><ref name="Sanchez-SpitmanSwen2019" />
| duration_of_action =
| excretion = [[Feces]]: 65%<br />[[Urine]]: 9%

<!-- Identifiers -->
| index2_label = citrate
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 10540-29-1
| CAS_number2 = 54965-24-1
| PubChem = 2733526
| PubChem2 = 2733525
| IUPHAR_ligand = 1016
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00675
| DrugBank2 = DBSALT000168
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 2015313
| ChemSpiderID2 = 2015312
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 094ZI81Y45
| UNII2 = 7FRV7310N6
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D08559
| KEGG2 = D00966
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 41774
| ChEBI2 = 9397
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 83
| ChEMBL2 = 786
| NIAID_ChemDB      =
| PDB_ligand        = CTX
| synonyms = TMX; ICI-46474

<!-- Chemical and physical data -->
| IUPAC_name = (''Z'')-2-[4-(1,2-Diphenylbut-1-enyl)phenoxy]-''N'',''N''-dimethylethanamine
| C=26 | H=29 | N=1 | O=1
| SMILES = CN(C)CCOc1ccc(cc1)/C(c2ccccc2)=C(/CC)c3ccccc3
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C26H29NO/c1-4-25(21-11-7-5-8-12-21)26(22-13-9-6-10-14-22)23-15-17-24(18-16-23)28-20-19-27(2)3/h5-18H,4,19-20H2,1-3H3/b26-25-
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = NKANXQFJJICGDU-QPLCGJKRSA-N
}}

<!-- Definition and medical uses -->
'''Tamoxifen''', sold under the brand name '''Nolvadex''' among others, is a [[selective estrogen receptor modulator]] used to prevent [[breast cancer]] in women and men.<ref name="NCI2015">{{Cite web |date=26 August 2015 |title=Tamoxifen Citrate |url=http://www.cancer.gov/about-cancer/treatment/drugs/tamoxifencitrate |url-status=live |archive-url=https://web.archive.org/web/20160104184533/http://www.cancer.gov/about-cancer/treatment/drugs/tamoxifencitrate |archive-date=4 January 2016 |access-date=28 November 2015 |website=NCI}}</ref> It is also being studied for other types of [[cancer]].<ref name=NCI2015/> It has been used for [[Albright syndrome]].<ref name=AHFS2015/> Tamoxifen is typically taken daily [[oral administration|by mouth]] for five years for breast cancer.<ref name="AHFS2015">{{Cite web |title=Tamoxifen Citrate |url=https://www.drugs.com/monograph/tamoxifen-citrate.html |url-status=live |archive-url=https://web.archive.org/web/20140104090258/http://www.drugs.com/monograph/tamoxifen-citrate.html |archive-date=4 January 2014 |access-date=27 November 2015 |website=The American Society of Health-System Pharmacists}}</ref>

<!-- Side effects -->
Serious side effects include a small increased risk of [[uterine cancer]], [[stroke]], vision problems, and [[pulmonary embolism]].<ref name=AHFS2015/> Common side effects include [[irregular menstruation|irregular periods]], weight loss, and [[hot flashes]].<ref name=AHFS2015/> It may cause harm to the baby if taken during [[pregnancy]] or [[breastfeeding]].<ref name=AHFS2015/> It is a [[selective estrogen-receptor modulator]] (SERM) and works by decreasing the growth of breast cancer cells.<ref name=AHFS2015/><ref>{{Cite web |title=Selective estrogen receptor modulators |url=https://www.drugs.com/drug-class/selective-estrogen-receptor-modulators.html |url-status=live |archive-url=https://web.archive.org/web/20131209195629/http://www.drugs.com/drug-class/selective-estrogen-receptor-modulators.html |archive-date=9 December 2013 |access-date=28 November 2015}}</ref> It is a member of the [[triphenylethylene]] group of [[chemical compound|compound]]s.<ref>{{Cite book |url=https://books.google.com/books?id=heJDAAAAQBAJ&pg=PA52 |title=Selective Estrogen Receptor Modulators a New Brand of Multitarget Drugs |date=2006 |publisher=Springer-Verlag Berlin Heidelberg |isbn=9783540347422 |veditors=Cano A, Calaf i Alsina J, Duenas-Diez JL |location=Berlin, Heidelberg |page=52}}</ref>

<!-- History, society and culture -->
Tamoxifen was initially made in 1962, by chemist [[Dora Richardson]].<ref name="Viviane M 2017" /><ref name="Jordan_2006">{{Cite journal |vauthors=Jordan VC |date=January 2006 |title=Tamoxifen (ICI46,474) as a targeted therapy to treat and prevent breast cancer |journal=British Journal of Pharmacology |volume=147 |issue=Suppl 1 |pages=S269–S276 |doi=10.1038/sj.bjp.0706399 |pmc=1760730 |pmid=16402113}}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO21st">{{Cite book |author-link=World Health Organization |title=World Health Organization model list of essential medicines: 21st list 2019 |vauthors=((World Health Organization)) |publisher=World Health Organization |year=2019 |location=Geneva |hdl=10665/325771 |id=WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO |hdl-access=free}}</ref> Tamoxifen is available as a [[generic medication]].<ref name=AHFS2015/>  In 2020, it was the 317th most commonly prescribed medication in the United States, with more than 900{{nbsp}}thousand prescriptions.<ref>{{Cite web |title=The Top 300 of 2020 |url=https://clincalc.com/DrugStats/Top300Drugs.aspx |access-date=7 October 2022 |website=ClinCalc}}</ref><ref>{{Cite web |title=Tamoxifen Citrate - Drug Usage Statistics |url=https://clincalc.com/DrugStats/Drugs/TamoxifenCitrate |url-status=dead |archive-url=https://web.archive.org/web/20200922010115/https://clincalc.com/DrugStats/Drugs/TamoxifenCitrate |archive-date=22 September 2020 |access-date=7 October 2022 |website=ClinCalc}}</ref>
{{TOC limit}}

==Medical uses==

===Dysmenorrhea===
[[Dysmenorrhea]] is the term for menstrual pain, usually centered in the lower abdomen but often spreading to the back and inner thighs. It is a common gynecological condition that can seriously affect daily activities and well-being. Tamoxifen has been identified and used to effectively improve blood flow, reduce uterine contractility and pain in dysmenorrhea patients.<ref name="modern">{{Cite journal |vauthors=Thomas B, Magos A |date=2009 |title=Modern management of dysmenorrhoea |journal=Trends in Urology, Gynaecology & Sexual Health |volume=14 |issue=5 |pages=25–29 |doi=10.1002/tre.120 |doi-access=free}}</ref><ref>{{Cite book |title=StatPearls |vauthors=Nagy H, Carlson K, Khan MA |date=2024 |publisher=StatPearls Publishing |location=Treasure Island (FL) |chapter=Dysmenorrhea |pmid=32809669 |access-date=1 October 2024 |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK560834/}}</ref>

===Breast cancer===
Tamoxifen is used for the treatment of both early and advanced [[estrogen receptor]]-positive (ER-positive or ER+) breast cancer in [[premenopausal|pre-]] and [[postmenopausal]] women.<ref name="Jordan_1993">{{Cite journal |vauthors=Jordan VC |date=October 1993 |title=Fourteenth Gaddum Memorial Lecture. A current view of tamoxifen for the treatment and prevention of breast cancer |journal=British Journal of Pharmacology |volume=110 |issue=2 |pages=507–517 |doi=10.1111/j.1476-5381.1993.tb13840.x |pmc=2175926 |pmid=8242225}}</ref> Tamoxifen increases the risk of [[Vaginal bleeding|postmenopausal bleeding]], [[endometrial polyp]]s, [[hyperplasia]], and [[endometrial cancer]]; using tamoxifen with an [[IntraUterine System|intrauterine system]] releasing [[levonorgestrel]] might increase vaginal bleeding after 1 to 2 years, but reduces somewhat endometrial polyps and hyperplasia, but not necessarily endometrial cancer.<ref>{{Cite journal |vauthors=Romero SA, Young K, Hickey M, Su HI |date=December 2020 |title=Levonorgestrel intrauterine system for endometrial protection in women with breast cancer on adjuvant tamoxifen |journal=The Cochrane Database of Systematic Reviews |volume=12 |issue=2 |pages=CD007245 |doi=10.1002/14651858.CD007245.pub4 |pmc=8092675 |pmid=33348436}}</ref> Additionally, it is the most common hormone treatment for male breast cancer.<ref name="urlBreast cancer in men: Cancer Research UK: CancerHelp UK">{{Cite web |date=28 September 2007 |title=Breast cancer in men |url=http://www.cancerhelp.org.uk/help/default.asp?page=5075 |url-status=dead |archive-url=https://web.archive.org/web/20081201175641/http://www.cancerhelp.org.uk/help/default.asp?page=5075 |archive-date=1 December 2008 |access-date=22 March 2009 |website=CancerHelp UK |publisher=Cancer Research UK}}</ref> It is also approved by the [[Food and Drug Administration|FDA]] for the prevention of breast cancer in women at high risk of developing the disease.<ref name="FDA">{{Cite web |last=Center for Drug Evaluation and Research |date=7 July 2005 |title=Tamoxifen Information: reducing the incidence of breast cancer in women at high risk |url=https://www.fda.gov/cder/news/tamoxifen/ |archive-url=https://web.archive.org/web/20070619012859/https://www.fda.gov/cder/news/tamoxifen/ |archive-date=19 June 2007 |access-date=3 July 2007 |publisher=U.S. Food and Drug Administration}}</ref> The effectiveness of tamoxifen is primarily influenced by estrogen receptor (ER) status, which was the key predictor of the proportional benefits observed. It has been further approved for the reduction of [[contralateral]] (in the opposite breast) cancer. Five years of adjuvant tamoxifen treatment significantly lowers the 15-year risk of breast cancer recurrence and mortality. The overall use of tamoxifen is recommended for 10 years.<ref>{{Cite journal |vauthors=Burstein HJ, Temin S, Anderson H, Buchholz TA, Davidson NE, Gelmon KE, Giordano SH, Hudis CA, Rowden D, Solky AJ, Stearns V, Winer EP, Griggs JJ |date=July 2014 |title=Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: american society of clinical oncology clinical practice guideline focused update |journal=Journal of Clinical Oncology |volume=32 |issue=21 |pages=2255–2269 |doi=10.1200/JCO.2013.54.2258 |pmc=4876310 |pmid=24868023}}</ref><ref>{{Cite journal |vauthors=Abe O, Abe R, Enomoto K, Kikuchi K, Koyama H, Masuda H, etal |date=August 2011 |title=Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials |journal=The Lancet |language=en |volume=378 |issue=9793 |pages=771–784 |doi=10.1016/S0140-6736(11)60993-8 |pmc=3163848 |pmid=21802721 |collaboration=Early Breast Cancer Trialists' Collaborative Group (EBCTCG)}}</ref>

In 2006, the large STAR clinical study concluded that [[raloxifene]] is also effective in reducing the incidence of breast cancer. Updated results after an average of 6.75 years of follow up found that raloxifene retains 76% of tamoxifen's effectiveness in preventing invasive breast cancer, with 45% fewer [[uterine cancer]]s and 25% fewer blood clots in women taking raloxifene than in women taking tamoxifen.<ref name="NCI">{{Cite web |last=National Cancer Institute |date=26 April 2006 |title=Study of Tamoxifen and Raloxifene (STAR) Trial |url=http://www.cancer.gov/star |url-status=dead |archive-url=https://web.archive.org/web/20070704091218/http://www.cancer.gov/star |archive-date=4 July 2007 |access-date=3 July 2007 |publisher=U.S. National Institutes of Health}}</ref><ref name="STAR">{{Cite web |last=University of Pittsburgh |title=STAR Study of Tamoxifen and Raloxifen |url=http://www.nsabp.pitt.edu/STAR/Index.html |archive-url=https://web.archive.org/web/20070611194336/http://www.nsabp.pitt.edu/STAR/Index.html |archive-date=11 June 2007 |access-date=3 July 2007}}</ref><ref>{{Cite web |author-link=Susan Love |date=22 April 2006 |title=Study Finds New Use for Raloxifene: Reducing Breast Cancer in High-Risk Postmenopausal Women |url=http://www.dslrf.org/breastcancer/content.asp?L2=2&L3=6&SID=130&CID=391&PID=14&CATID=0 |url-status=dead |archive-url=https://web.archive.org/web/20090802013050/http://www.dslrf.org/breastcancer/content.asp?L2=2&L3=6&SID=130&CID=391&PID=14&CATID=0 |archive-date=2 August 2009 |access-date=19 March 2009 |vauthors=Love S}}</ref>

===Infertility===
Tamoxifen is used for [[ovulation induction]] to treat infertility in women with [[anovulatory cycle|anovulatory]] disorders. It is given at days three to seven of a woman's cycle.<ref name="Steiner_2005">{{Cite journal |vauthors=Steiner AZ, Terplan M, Paulson RJ |date=June 2005 |title=Comparison of tamoxifen and clomiphene citrate for ovulation induction: a meta-analysis |journal=Human Reproduction |volume=20 |issue=6 |pages=1511–1515 |doi=10.1093/humrep/deh840 |pmid=15845599 |doi-access=free}}</ref>

Tamoxifen improves fertility in males with infertility by disinhibiting the [[hypothalamic–pituitary–gonadal axis]] (HPG axis) via ER antagonism and thereby increasing the secretion of [[luteinizing hormone]] (LH) and [[follicle-stimulating hormone]] (FSH) and increasing testicular [[testosterone]] production.<ref name="pmid23970453">{{Cite journal |vauthors=Chua ME, Escusa KG, Luna S, Tapia LC, Dofitas B, Morales M |date=September 2013 |title=Revisiting oestrogen antagonists (clomiphene or tamoxifen) as medical empiric therapy for idiopathic male infertility: a meta-analysis |journal=Andrology |volume=1 |issue=5 |pages=749–757 |doi=10.1111/j.2047-2927.2013.00107.x |pmid=23970453 |s2cid=38345293 |doi-access=free}}</ref> Some animal studies have suggested tamoxifen could have negative effects on sperm quality and prostatic and gonadal health.<ref>{{Cite journal |vauthors=Sadeghi S, Reza Talebi A, Shahedi A, Reza Moein Md M, Abbasi-Sarcheshmeh A |date=April 2019 |title=Effects of different doses of tamoxifen on the sperm parameters and chromatin quality in mice: An experimental model |journal=International Journal of Reproductive Biomedicine |volume=17 |issue=4 |pages=279–286 |doi=10.18502/ijrm.v17i4.4553 |pmc=6686649 |pmid=31435602}}</ref><ref>{{Cite journal |vauthors=Corrada Y, Arias D, Rodríguez R, Spaini E, Fava F, Gobello C |date=May 2004 |title=Effect of tamoxifen citrate on reproductive parameters of male dogs |journal=Theriogenology |volume=61 |issue=7–8 |pages=1327–1341 |doi=10.1016/j.theriogenology.2003.07.020 |pmid=15036966}}</ref>

===Gynecomastia===
Benign enlargement of the male breast, whether [[asymptomatic]] or painful, is a common condition thought to result from an increased estrogen/testosterone ratio or from heightened [[estrogen]]ic or reduced [[androgen]]ic activity via receptor interactions.Tamoxifen is used to prevent and treat [[gynecomastia]].<ref name="Lapidvan Wingerden2013">{{Cite journal |vauthors=Lapid O, van Wingerden JJ, Perlemuter L |year=2013 |title=Tamoxifen therapy for the management of pubertal gynecomastia: a systematic review |journal=Journal of Pediatric Endocrinology & Metabolism |volume=26 |issue=9–10 |pages=803–807 |doi=10.1515/jpem-2013-0052 |pmid=23729603 |s2cid=2101602}}</ref><ref name="VianiBernardes da Silva2012">{{Cite journal |vauthors=Viani GA, Bernardes da Silva LG, Stefano EJ |date=July 2012 |title=Prevention of gynecomastia and breast pain caused by androgen deprivation therapy in prostate cancer: tamoxifen or radiotherapy? |journal=International Journal of Radiation Oncology, Biology, Physics |volume=83 |issue=4 |pages=e519–e524 |doi=10.1016/j.ijrobp.2012.01.036 |pmid=22704706}}</ref> It is taken as a preventative measure in small doses, or used at the onset of any symptoms such as nipple soreness or sensitivity. Current treatments typically involve pain relief through medication or surgery. However, targeting the underlying estrogenic stimulation may offer a more specific therapeutic approach. In a double-blind crossover study, patients were given either a placebo or tamoxifen (10 mg orally twice daily) for one month, in random order. Seven out of ten patients saw a reduction in gynecomastia size with tamoxifen (P < 0.005), and the overall reduction for the group was statistically significant (P < 0.01).<ref>{{Cite journal |vauthors=Parker LN, Gray DR, Lai MK, Levin ER |date=August 1986 |title=Treatment of gynecomastia with tamoxifen: a double-blind crossover study |journal=Metabolism |volume=35 |issue=8 |pages=705–708 |doi=10.1016/0026-0495(86)90237-4 |pmid=3526085}}</ref> No benefits were observed with the placebo (P > 0.1). Additionally, all four patients with painful gynecomastia experienced relief of their symptoms, and no toxicity was noted. Although the breast size reduction was partial, this suggests that longer treatment may be necessary. Follow-up examinations conducted 9 to 12 months after treatment revealed no significant changes, except in two cases: one tamoxifen responder had a recurrence of breast tenderness after six months, and one non-responder developed increased breast size and new tenderness after ten months. Other medications are taken for similar purposes such as [[clomifene]] and [[aromatase inhibitor]] drugs; which are used in order to try to avoid the hormone-related adverse effects. Overall, tamoxifen appears to be a safe and effective treatment option for selected cases of gynecomastia.{{cn|date=January 2025}}

{{Tamoxifen dosage and incidence of breast symptoms with bicalutamide in men}}

===Early puberty===
Tamoxifen is useful in the treatment of [[peripheral precocious puberty]], for instance due to [[McCune–Albright syndrome]], in both girls and boys.<ref name="pmid29292624">{{Cite journal |vauthors=Neyman A, Eugster EA |date=December 2017 |title=Treatment of Girls and Boys with McCune-Albright Syndrome with Precocious Puberty - Update 2017 |journal=Pediatric Endocrinology Reviews |volume=15 |issue=2 |pages=136–141 |doi=10.17458/per.vol15.2017.nau.treatmentgirlsboys |pmc=5808444 |pmid=29292624}}</ref><ref name="HaddadEugster2019">{{Cite journal |vauthors=Haddad NG, Eugster EA |date=June 2019 |title=Peripheral precocious puberty including congenital adrenal hyperplasia: causes, consequences, management and outcomes |journal=Best Practice & Research. Clinical Endocrinology & Metabolism |volume=33 |issue=3 |pages=101273 |doi=10.1016/j.beem.2019.04.007 |pmid=31027974 |s2cid=135410503 |hdl-access=free |hdl=1805/19111}}</ref><ref name="Zacharin2019">{{Cite book |title=Pediatric Pharmacotherapy |vauthors=Zacharin M |date=May 2019 |isbn=978-3-030-50493-9 |series=Handbook of Experimental Pharmacology |volume=261 |pages=507–538 |chapter=Disorders of Puberty: Pharmacotherapeutic Strategies for Management |doi=10.1007/164_2019_208 |pmid=31144045 |s2cid=169040406}}</ref> It has been found to decrease [[growth velocity]] and the rate of [[bone maturation]] in girls with precocious puberty, and hence to improve final [[human height|height]] in these individuals.<ref name="pmid29292624" /><ref name="HaddadEugster2019" />

===Available forms===
[[File:Nolvadex.jpg|thumb|right|250px|Nolvadex (tamoxifen) 20 mg tablets.]]

Tamoxifen is available as a tablet or oral solution.<ref>Product Information: tamoxifen citrate oral tablets, tamoxifen citrate oral tablets. Watson Laboratories (per manufacturer), Corona, CA, 2011.</ref><ref>Product Information: SOLTAMOX(R) oral solution, tamoxifen citrate oral solution. Midatech Pharma US Inc (per FDA), Raleigh, NC, 2018.</ref>

==Contraindications==
Tamoxifen has a number of [[contraindication]]s, including known [[hypersensitivity]] to tamoxifen or other ingredients, individuals taking concomitant [[coumarin]]-type [[anticoagulant]] therapy, and women with a history of [[venous thromboembolism]] ([[deep vein thrombosis]] or [[pulmonary embolism]]).<ref name="Nolvadex-Label" />

==Side effects==
A report in September 2009 from Health and Human Services' Agency for Healthcare Research and Quality suggests that tamoxifen, raloxifene, and tibolone used to treat breast cancer significantly reduce invasive breast cancer in midlife and older women, but also increase the risk of adverse side effects.<ref>{{Cite web |last=OncoGenetics.Org |date=September 2009 |title=Medications Effective in Reducing Risk of Breast Cancer But Increase Risk of Adverse Effects |url=http://www.oncogenetics.org/web/Medications-Effective-in-Reducing-Risk-of-Breast-Cancer-But-Increase-Risk-of-Adverse-Effects |url-status=dead |archive-url=https://web.archive.org/web/20090924092345/http://www.oncogenetics.org/web/Medications-Effective-in-Reducing-Risk-of-Breast-Cancer-But-Increase-Risk-of-Adverse-Effects |archive-date=24 September 2009 |access-date=14 September 2009 |publisher=OncoGenetics.Org}}</ref>

===Endometrial cancer===
Tamoxifen is a [[selective estrogen receptor modulator]] (SERM).<ref name="Gallo_1997">{{Cite journal |vauthors=Gallo MA, Kaufman D |date=February 1997 |title=Antagonistic and agonistic effects of tamoxifen: significance in human cancer |journal=Seminars in Oncology |volume=24 |issue=1 Suppl 1 |pages=S1-71-S1-80 |pmid=9045319}}</ref> Even though it is an [[receptor antagonist|antagonist]] in breast tissue it acts as [[partial agonist]] on the [[endometrium]] and has been linked to [[endometrial cancer]] in some women. Therefore, endometrial changes, including cancer, are among tamoxifen's side effects.<ref name="Grilli_2006">{{Cite journal |vauthors=Grilli S |year=2006 |title=Tamoxifen (TAM): the dispute goes on |url=http://www.iss.it/publ/anna/2006/2/422170.pdf |url-status=dead |journal=Annali dell'Istituto Superiore di Sanità |volume=42 |issue=2 |pages=170–173 |pmid=17033137 |archive-url=https://web.archive.org/web/20070810113431/http://www.iss.it/publ/anna/2006/2/422170.pdf |archive-date=10 August 2007 |access-date=3 July 2007}}</ref> With time, risk of endometrial cancer may be doubled to quadrupled, which is a reason tamoxifen is typically only used for five years.<ref>{{Cite web |date=11 December 2009 |title=Tamoxifen for Breast Cancer & Side Effects |url=http://healthlifeandstuff.com/2009/12/tamoxifen-for-breast-cancer-side-effects/ |url-status=live |archive-url=https://web.archive.org/web/20100216232531/http://healthlifeandstuff.com/2009/12/tamoxifen-for-breast-cancer-side-effects/ |archive-date=16 February 2010 |publisher=Health and Life}}</ref>

The [[American Cancer Society]] lists tamoxifen as a known [[carcinogen]], stating that it increases the risk of some types of uterine cancer while lowering the risk of breast cancer recurrence.<ref name="ACS">{{Cite web |date=3 February 2006 |title=Known and Probable Carcinogens |url=http://www.cancer.org/docroot/PED/content/PED_1_3x_Known_and_Probable_Carcinogens.asp?sitearea=PED |url-status=live |archive-url=https://web.archive.org/web/20080317051133/http://www.cancer.org/docroot/PED/content/PED_1_3x_Known_and_Probable_Carcinogens.asp?sitearea=PED |archive-date=17 March 2008 |access-date=21 March 2008 |publisher=American Cancer Society}}</ref>

===Cardiovascular and metabolic===
Tamoxifen treatment of postmenopausal women is associated with beneficial effects on serum lipid profiles. However, long-term data from clinical trials have failed to demonstrate a cardioprotective effect.<ref name="pmid16230014">{{Cite journal |vauthors=Esteva FJ, Hortobagyi GN |date=June 2006 |title=Comparative assessment of lipid effects of endocrine therapy for breast cancer: implications for cardiovascular disease prevention in postmenopausal women |journal=Breast |volume=15 |issue=3 |pages=301–312 |doi=10.1016/j.breast.2005.08.033 |pmid=16230014}}</ref> For some women, tamoxifen can cause a rapid increase in [[triglyceride]] concentration in the blood. In addition, there is an increased risk of [[thromboembolism]] especially during and immediately after major surgery or periods of immobility.<ref name="pmid15699284">{{Cite journal |vauthors=Decensi A, Maisonneuve P, Rotmensz N, Bettega D, Costa A, Sacchini V, Salvioni A, Travaglini R, Oliviero P, D'Aiuto G, Gulisano M, Gucciardo G, del Turco MR, Pizzichetta MA, Conforti S, Bonanni B, Boyle P, Veronesi U |date=February 2005 |title=Effect of tamoxifen on venous thromboembolic events in a breast cancer prevention trial |journal=Circulation |volume=111 |issue=5 |pages=650–656 |doi=10.1161/01.CIR.0000154545.84124.AC |pmid=15699284 |doi-access=free}}</ref> Use of tamoxifen has been shown to slightly increase risk of [[deep vein thrombosis]], [[pulmonary embolism]], and [[stroke]].<ref name="Harvey_2006">{{Cite journal |vauthors=Harvey HA, Kimura M, Hajba A |date=April 2006 |title=Toremifene: an evaluation of its safety profile |journal=Breast |volume=15 |issue=2 |pages=142–157 |doi=10.1016/j.breast.2005.09.007 |pmid=16289904}}</ref>

===Liver toxicity===
Tamoxifen has been associated with a number of cases of [[hepatotoxicity]].<ref name="CameronFeuer2012">{{Cite book |url=https://books.google.com/books?id=xZf-CAAAQBAJ&pg=PA565 |title=Drug-Induced Hepatotoxicity |vauthors=Cameron R, Feuer G, de la Iglesia F |date=6 December 2012 |publisher=Springer Science & Business Media |isbn=978-3-642-61013-4 |pages=565–}}</ref> Several different varieties of hepatotoxicity have been reported.<ref name="CameronFeuer2012" /> Tamoxifen can also precipitate [[non-alcoholic fatty liver disease]] in obese and overweight women (not in normal weight women) at an average rate of 40% after a year use with 20&nbsp;mg/day.<ref name="pmid17181445">{{Cite journal |vauthors=Osman KA, Osman MM, Ahmed MH |date=January 2007 |title=Tamoxifen-induced non-alcoholic steatohepatitis: where are we now and where are we going? |journal=Expert Opinion on Drug Safety |volume=6 |issue=1 |pages=1–4 |doi=10.1517/14740338.6.1.1 |pmid=17181445 |s2cid=33505288}}</ref>

==Overdose==
Acute [[overdose]] of tamoxifen has not been reported in humans.<ref name="Nolvadex-Label" /> In [[dose-ranging study|dose-ranging studies]], tamoxifen was administered at very high doses in women (e.g., 300&nbsp;mg/m<sup>2</sup>) and was found to produce acute [[neurotoxicity]] including [[tremor]], [[hyperreflexia]], [[gait abnormality|unsteady gait]], and [[dizziness]].<ref name="Nolvadex-Label" /> These symptoms occurred within three to five days of therapy and disappeared within two to five days of discontinuation of therapy.<ref name="Nolvadex-Label" /> No indications of permanent neurotoxicity were observed.<ref name="Nolvadex-Label" /> [[QT prolongation]] was also observed with very high doses of tamoxifen.<ref name="Nolvadex-Label" /> There is no specific [[antidote]] for overdose of tamoxifen.<ref name="Nolvadex-Label" /> Instead, treatment should be based on [[symptom]]s.<ref name="Nolvadex-Label" />

== Interactions ==

Patients with variant forms of the gene [[CYP2D6]] may not receive full benefit from tamoxifen because of too slow metabolism of the tamoxifen prodrug into its active metabolites.<ref name="Goetz_2005">{{Cite journal |vauthors=Goetz MP, Rae JM, Suman VJ, Safgren SL, Ames MM, Visscher DW, Reynolds C, Couch FJ, Lingle WL, Flockhart DA, Desta Z, Perez EA, Ingle JN |date=December 2005 |title=Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes |journal=Journal of Clinical Oncology |volume=23 |issue=36 |pages=9312–9318 |doi=10.1200/JCO.2005.03.3266 |pmid=16361630 |doi-access=free}}</ref><ref name="Beverage_2007">{{Cite journal |vauthors=Beverage JN, Sissung TM, Sion AM, Danesi R, Figg WD |date=September 2007 |title=CYP2D6 polymorphisms and the impact on tamoxifen therapy |journal=Journal of Pharmaceutical Sciences |volume=96 |issue=9 |pages=2224–2231 |doi=10.1002/jps.20892 |pmid=17518364}}</ref> On 18 October 2006, the Subcommittee for Clinical Pharmacology recommended relabeling tamoxifen to include information about this gene in the package insert.<ref>[http://talk.dnadirect.com/2006/10/19/genetic-test-for-response-to-tamoxifen/ Information about CYP2D6 and tamoxifen from DNADirect's website] {{webarchive|url=https://web.archive.org/web/20070311134122/http://talk.dnadirect.com/2006/10/19/genetic-test-for-response-to-tamoxifen/ |date=11 March 2007 }}</ref> Certain CYP2D6 variations in breast cancer patients lead to a worse clinical outcome for tamoxifen treatment.<ref name="pmid19809024">{{Cite journal |vauthors=Schroth W, Goetz MP, Hamann U, Fasching PA, Schmidt M, Winter S, Fritz P, Simon W, Suman VJ, Ames MM, Safgren SL, Kuffel MJ, Ulmer HU, Boländer J, Strick R, Beckmann MW, Koelbl H, Weinshilboum RM, Ingle JN, Eichelbaum M, Schwab M, Brauch H |date=October 2009 |title=Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen |journal=JAMA |volume=302 |issue=13 |pages=1429–1436 |doi=10.1001/jama.2009.1420 |pmc=3909953 |pmid=19809024}}</ref> [[Genotyping]] therefore has the potential for identification of women who have these CYP2D6 phenotypes and for whom the use of tamoxifen is associated with poor outcomes. Recent research has shown that 7–10% of women with breast cancer may not receive the full medical benefit from taking tamoxifen due to their genetic make-up. DNA Drug Safety Testing can examine DNA variations in the CYP2D6 and other important drug processing pathways. More than 20% of all clinically used medications are metabolized by CYP2D6 and knowing the CYP2D6 status of a person can help the doctor with the future selection of medications.<ref>[http://www.tamoxitest.com/what_is_tamoxitest.html Information about Tamoxitest and how DNA testing can help in the selection of the best treatment methodology from Genelex's website] {{webarchive|url=https://web.archive.org/web/20100527152154/http://www.tamoxitest.com/what_is_tamoxitest.html |date=27 May 2010 }}</ref> Other molecular biomarkers may also be used to select appropriate patients likely to benefit from tamoxifen.<ref name="pmid21552410">{{Cite journal |vauthors=Criscitiello C, Fumagalli D, Saini KS, Loi S |date=December 2010 |title=Tamoxifen in early-stage estrogen receptor-positive breast cancer: overview of clinical use and molecular biomarkers for patient selection |journal=OncoTargets and Therapy |volume=4 |pages=1–11 |doi=10.2147/OTT.S10155 |pmc=3084302 |pmid=21552410 |doi-access=free}}</ref>

Recent studies suggest that taking the [[selective serotonin reuptake inhibitors]] (SSRIs) antidepressants [[paroxetine]] (Paxil), [[fluoxetine]] (Prozac), and [[sertraline]] (Zoloft) can decrease the effectiveness of tamoxifen, as these drugs compete for the CYP2D6 enzyme which is needed to metabolize tamoxifen into its active forms.<ref name="Jin_2005">{{Cite journal |vauthors=Jin Y, Desta Z, Stearns V, Ward B, Ho H, Lee KH, Skaar T, Storniolo AM, Li L, Araba A, Blanchard R, Nguyen A, Ullmer L, Hayden J, Lemler S, Weinshilboum RM, Rae JM, Hayes DF, Flockhart DA |date=January 2005 |title=CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment |journal=Journal of the National Cancer Institute |volume=97 |issue=1 |pages=30–39 |doi=10.1093/jnci/dji005 |pmid=15632378 |doi-access=free}}</ref> A U.S. study presented at the American Society of Clinical Oncology's annual meeting in 2009 found that after two years, 7.5% of women who took only tamoxifen had a recurrence, compared with 16% who took either paroxetine, fluoxetine or sertraline, drugs considered to be the most potent CYP2D6 inhibitors. That difference translates to a 120% increase in the risk of breast cancer recurrence. Patients taking the SSRIs Celexa ([[citalopram]]), Lexapro ([[escitalopram]]), and Luvox ([[fluvoxamine]]) did not have an increased risk of recurrence, due to their lack of competitive metabolism for the CYP2D6 enzyme.<ref>{{Cite news |last=Staff Reports |date=Summer 2009 |title=ASCO Updates: Antidepressants Reduce the Effectiveness of Tamoxifen. |url=http://www.curetoday.com/index.cfm/fuseaction/article.show/id/2/article_id/1152 |url-status=live |archive-url=https://web.archive.org/web/20090622192239/http://www.curetoday.com/index.cfm/fuseaction/article.show/id/2/article_id/1152 |archive-date=22 June 2009 |publisher=CURE (Cancer Updates, Research and Education)}}</ref> A newer study demonstrated a clearer and stronger effect from paroxetine in causing the worst outcomes. Patients treated with both paroxetine and tamoxifen have a 67% increased risk of death from breast cancer, from 24% to 91%, depending on the duration of coadministration.<ref>{{Cite journal |vauthors=Kelly CM, Juurlink DN, Gomes T, Duong-Hua M, Pritchard KI, Austin PC, Paszat LF |date=February 2010 |title=Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study |journal=BMJ |volume=340 |pages=c693 |doi=10.1136/bmj.c693 |pmc=2817754 |pmid=20142325}}</ref>

Tamoxifen interacts with certain other [[antiestrogen]]s.<ref name="MorelloWurz2003" /> The [[aromatase inhibitor]] [[aminoglutethimide]] induces the metabolism of tamoxifen.<ref name="MorelloWurz2003" /> Conversely, the aromatase inhibitor [[letrozole]] does not affect the metabolism of tamoxifen.<ref name="MorelloWurz2003" /> However, tamoxifen induces the metabolism of letrozole and significantly reduces its concentrations.<ref name="MorelloWurz2003" />

==Pharmacology==

===Pharmacodynamics===

====Selective estrogen receptor modulator activity====
[[Image:3ert.png|thumb|[[X-ray crystallography#Biological macromolecular crystallography|Crystallographic structure]] of afimoxifene ([[carbon]] = white, [[oxygen]] = red, [[nitrogen]] = blue) complexed with [[Nuclear receptor#Structure|ligand binding domain]] of [[estrogen receptor alpha]] (ERα) (cyan ribbon).<ref name="pmid9875847">{{PDB|3ERT}}; {{Cite journal |vauthors=Shiau AK, Barstad D, Loria PM, Cheng L, Kushner PJ, Agard DA, Greene GL |date=December 1998 |title=The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen |journal=Cell |volume=95 |issue=7 |pages=927–937 |doi=10.1016/S0092-8674(00)81717-1 |pmid=9875847 |s2cid=10265320 |doi-access=free}}</ref>]]

Tamoxifen acts as a [[selective estrogen receptor modulator]] (SERM), or as a [[partial agonist]] of the [[estrogen receptor]]s (ERs). It has mixed [[estrogen (medication)|estrogen]]ic and [[antiestrogen]]ic activity, with its profile of effects differing by [[tissue (biology)|tissue]]. For instance, tamoxifen has predominantly antiestrogenic effects in the [[breast]]s but predominantly estrogenic effects in the [[uterus]] and [[liver]]. In breast tissue, tamoxifen acts as an ER [[receptor antagonist|antagonist]] so that [[gene transcription|transcription]] of estrogen-responsive genes is inhibited.<ref name="Wang_2004">{{Cite journal |vauthors=Wang DY, Fulthorpe R, Liss SN, Edwards EA |date=February 2004 |title=Identification of estrogen-responsive genes by complementary deoxyribonucleic acid microarray and characterization of a novel early estrogen-induced gene: EEIG1 |journal=Molecular Endocrinology |volume=18 |issue=2 |pages=402–411 |doi=10.1210/me.2003-0202 |pmid=14605097 |doi-access=free}}</ref> A beneficial side effect of tamoxifen is that it prevents bone loss by acting as an ER [[agonist]] (i.e., mimicking the effects of estrogen) in this cell type. Therefore, by inhibiting [[osteoclasts]], it prevents [[osteoporosis]].<ref name="pmid17803905">{{Cite journal |vauthors=Nakamura T, Imai Y, Matsumoto T, Sato S, Takeuchi K, Igarashi K, Harada Y, Azuma Y, Krust A, Yamamoto Y, Nishina H, Takeda S, Takayanagi H, Metzger D, Kanno J, Takaoka K, Martin TJ, Chambon P, Kato S |date=September 2007 |title=Estrogen prevents bone loss via estrogen receptor alpha and induction of Fas ligand in osteoclasts |journal=Cell |volume=130 |issue=5 |pages=811–823 |doi=10.1016/j.cell.2007.07.025 |pmid=17803905 |s2cid=17177462 |doi-access=free}}</ref><ref name="pmid18219273">{{Cite journal |vauthors=Krum SA, Miranda-Carboni GA, Hauschka PV, Carroll JS, Lane TF, Freedman LP, Brown M |date=February 2008 |title=Estrogen protects bone by inducing Fas ligand in osteoblasts to regulate osteoclast survival |journal=The EMBO Journal |volume=27 |issue=3 |pages=535–545 |doi=10.1038/sj.emboj.7601984 |pmc=2241656 |pmid=18219273}}</ref> When tamoxifen was launched as a drug, it was thought that tamoxifen would act as an ER antagonist in all tissues, including bone, and therefore it was feared that it would contribute to osteoporosis. It was therefore very surprising that the opposite effect was observed clinically. Hence tamoxifen's tissue selective action directly led to the formulation of the concept of SERMs.<ref name="Mincey_2000">{{Cite journal |vauthors=Mincey BA, Moraghan TJ, Perez EA |date=August 2000 |title=Prevention and treatment of osteoporosis in women with breast cancer |journal=Mayo Clinic Proceedings |volume=75 |issue=8 |pages=821–829 |doi=10.4065/75.8.821 |pmid=10943237 |doi-access=free}}</ref>

{{Tissue-specific estrogenic and antiestrogenic activity of SERMs}}

Tamoxifen is a long-acting SERM, with a [[nuclear retention]] of the ER–tamoxifen (or metabolite) complex of greater than 48&nbsp;hours.<ref name="RunnebaumRabe2013">{{Cite book |url=https://books.google.com/books?id=mBF9BwAAQBAJ&pg=PA88 |title=Gynäkologische Endokrinologie und Fortpflanzungsmedizin: Band 1: Gynäkologische Endokrinologie |vauthors=Runnebaum B, Rabe T |date=17 April 2013 |publisher=Springer-Verlag |isbn=978-3-662-07635-4 |pages=88–}}</ref><ref name="WallachHammond1982">{{Cite journal |vauthors=Hammond CB, Maxson WS |date=January 1982 |title=Current status of estrogen therapy for the menopause |journal=Fertility and Sterility |volume=37 |issue=1 |pages=5–25 |doi=10.1016/S0015-0282(16)45970-4 |pmid=6277697 |doi-access=free}}</ref> It has relatively little [[affinity (pharmacology)|affinity]] for the ERs itself and instead acts as a [[prodrug]] of [[active metabolite]]s such as [[endoxifen]] (4-hydroxy-''N''-desmethyltamoxifen) and [[afimoxifene]] (4-hydroxytamoxifen; 4-OHT).<ref name="pmid23962908" /> These metabolites have approximately 30 to 100 times greater affinity for the ERs than tamoxifen itself.<ref name="Sanchez-SpitmanSwen2019" /><ref name="pmid20981001">{{Cite journal |vauthors=Ahmad A, Shahabuddin S, Sheikh S, Kale P, Krishnappa M, Rane RC, Ahmad I |date=December 2010 |title=Endoxifen, a new cornerstone of breast cancer therapy: demonstration of safety, tolerability, and systemic bioavailability in healthy human subjects |journal=Clinical Pharmacology and Therapeutics |volume=88 |issue=6 |pages=814–817 |doi=10.1038/clpt.2010.196 |pmid=20981001 |s2cid=24590365}}</ref> Per one study, tamoxifen had 7% and 6% of the affinity of [[estradiol]] for the [[ERα]] and [[ERβ]], respectively, whereas afimoxifene had 178% and 338% of the affinity of estradiol for the ERα and ERβ, respectively.<ref name="pmid16112947">{{Cite journal |vauthors=Kuhl H |date=August 2005 |title=Pharmacology of estrogens and progestogens: influence of different routes of administration |journal=Climacteric |volume=8 |issue=Suppl 1 |pages=3–63 |doi=10.1080/13697130500148875 |pmid=16112947 |s2cid=24616324}}</ref> Hence, afimoxifene showed 25-fold higher affinity for the ERα and 56-fold higher affinity for the ERβ than tamoxifen.<ref name="pmid15863530">{{Cite journal |vauthors=Potts RO, Lobo RA |date=May 2005 |title=Transdermal drug delivery: clinical considerations for the obstetrician-gynecologist |journal=Obstetrics and Gynecology |volume=105 |issue=5 Pt 1 |pages=953–961 |doi=10.1097/01.AOG.0000161958.70059.db |pmid=15863530 |s2cid=23411589}}</ref> The antiestrogenic potencies of endoxifen and afimoxifene are very similar.<ref name="pmid23962908" /> However, endoxifen occurs in much higher concentrations than afimoxifene and is now thought to be the major active form of tamoxifen in the body.<ref name="Sanchez-SpitmanSwen2019" /><ref name="pmid23962908" /><ref name="pmid25618289">{{Cite journal |vauthors=Binkhorst L, Mathijssen RH, Jager A, van Gelder T |date=March 2015 |title=Individualization of tamoxifen therapy: much more than just CYP2D6 genotyping |journal=Cancer Treatment Reviews |volume=41 |issue=3 |pages=289–299 |doi=10.1016/j.ctrv.2015.01.002 |pmid=25618289}}</ref>

Tamoxifen binds to ER competitively (with respect to the endogenous agonist estrogen) in tumor cells and other tissue targets, producing a nuclear complex that decreases DNA synthesis and inhibits estrogen effects. It is a nonsteroidal agent with potent antiestrogenic properties which compete with estrogen for [[Cell signaling|binding sites]] in breast and other tissues. Tamoxifen causes cells to remain in the G<sub>0</sub> and G<sub>1</sub> phases of the [[cell cycle]]. Because it prevents (pre)cancerous cells from dividing but does not cause cell death, tamoxifen is cytostatic rather than cytocidal. Tamoxifen binds to ER, the ER/tamoxifen complex recruits other proteins known as [[corepressor (genetics)|co-repressors]], and the complex then binds to DNA to modulate gene expression. Some of these proteins include [[nuclear receptor co-repressor 1|NCoR]] and [[nuclear receptor co-repressor 2|SMRT]].<ref name="pmid11136970">{{Cite journal |vauthors=Shang Y, Hu X, DiRenzo J, Lazar MA, Brown M |date=December 2000 |title=Cofactor dynamics and sufficiency in estrogen receptor-regulated transcription |journal=Cell |volume=103 |issue=6 |pages=843–852 |doi=10.1016/S0092-8674(00)00188-4 |pmid=11136970 |s2cid=6659079 |doi-access=free}}</ref> Tamoxifen function can be regulated by a number of different variables including growth factors.<ref name="pmid18245484">{{Cite journal |vauthors=Massarweh S, Osborne CK, Creighton CJ, Qin L, Tsimelzon A, Huang S, Weiss H, Rimawi M, Schiff R |date=February 2008 |title=Tamoxifen resistance in breast tumors is driven by growth factor receptor signaling with repression of classic estrogen receptor genomic function |journal=Cancer Research |volume=68 |issue=3 |pages=826–833 |doi=10.1158/0008-5472.CAN-07-2707 |pmid=18245484 |doi-access=free}}</ref> Tamoxifen needs to block growth factor proteins such as [[ERBB2|ErbB2/HER2]]<ref name="Hurtado_2008">{{Cite journal |vauthors=Hurtado A, Holmes KA, Geistlinger TR, Hutcheson IR, Nicholson RI, Brown M, Jiang J, Howat WJ, Ali S, Carroll JS |date=December 2008 |title=Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen |journal=Nature |volume=456 |issue=7222 |pages=663–666 |bibcode=2008Natur.456..663H |doi=10.1038/nature07483 |pmc=2920208 |pmid=19005469}}</ref> because high levels of ErbB2 have been shown to occur in tamoxifen resistant cancers.<ref name="pmid12618500">{{Cite journal |vauthors=Osborne CK, Bardou V, Hopp TA, Chamness GC, [[Susan Hilsenbeck|Hilsenbeck SG]], Fuqua SA, Wong J, Allred DC, Clark GM, Schiff R |date=March 2003 |title=Role of the estrogen receptor coactivator AIB1 (SRC-3) and HER-2/neu in tamoxifen resistance in breast cancer |journal=Journal of the National Cancer Institute |volume=95 |issue=5 |pages=353–361 |doi=10.1093/jnci/95.5.353 |pmid=12618500 |doi-access=free}}</ref> Tamoxifen seems to require a protein [[PAX2]] for its full anticancer effect.<ref name="Hurtado_2008" /><ref name="urlwww.modernmedicine.com">{{Cite web |date=13 November 2008 |title=New Mechanism Predicts Tamoxifen Response: PAX2 gene implicated in tamoxifen-induced inhibition of ERBB2/HER2-mediated tumor growth |url=http://www.modernmedicine.com/modernmedicine/Modern+Medicine+Now/New-Mechanism-Predicts-Tamoxifen-Response/ArticleNewsFeed/Article/detail/565990 |url-status=live |archive-url=https://web.archive.org/web/20110714111141/http://www.modernmedicine.com/modernmedicine/Modern+Medicine+Now/New-Mechanism-Predicts-Tamoxifen-Response/ArticleNewsFeed/Article/detail/565990 |archive-date=14 July 2011 |access-date=14 November 2008 |publisher=www.modernmedicine.com}}</ref> In the presence of high PAX2 expression, the tamoxifen/ER complex is able to suppress the expression of the pro-proliferative [[HER2/neu|ERBB2]] protein. In contrast, when [[AIB-1]] expression is higher than PAX2, tamoxifen/ER complex upregulates the expression of ERBB2 resulting in stimulation of breast cancer growth.<ref name="Hurtado_2008" /><ref name="urlCORDIS : News">{{Cite web |title=Study sheds new light on tamoxifen resistance |url=http://cordis.europa.eu/fetch?CALLER=EN_NEWS&ACTION=D&SESSION=&RCN=30093 |url-status=live |archive-url=https://web.archive.org/web/20090220060249/http://cordis.europa.eu/fetch?CALLER=EN_NEWS&ACTION=D&SESSION=&RCN=30093 |archive-date=20 February 2009 |access-date=14 November 2008 |website=News |publisher=CORDIS News}}</ref>

Tamoxifen is [[antigonadotropic]] in [[postmenopausal]] women and partially suppresses levels of the [[gonadotropin]]s, [[luteinizing hormone]] (LH) and [[follicle-stimulating hormone]] (FSH) in such women.<ref name="pmid23687971" /> However, it has [[progonadotropic]] effects in [[premenopausal]] women and increases estrogen levels by 6-fold in them.<ref name="pmid23687971">{{Cite journal |vauthors=Li J, Ma Z, Jiang RW, Wu B |date=September 2013 |title=Hormone-related pharmacokinetic variations associated with anti-breast cancer drugs |journal=Expert Opinion on Drug Metabolism & Toxicology |volume=9 |issue=9 |pages=1085–1095 |doi=10.1517/17425255.2013.802771 |pmid=23687971 |s2cid=26846314}}</ref> Due to the nature of tamoxifen as a competitive ER ligand, this increase in estrogen levels is liable to interfere with the antiestrogenic efficacy of tamoxifen.<ref name="pmid23687971" /> The effects of tamoxifen on [[breast cancer]] [[Ki-67 (protein)|Ki-67]] [[gene expression|expression]], [[sex hormone-binding globulin]] (SHBG) levels, and IGF-1 levels are [[dose–response relationship|dose-dependent]] across a dosage range of 1 to 20&nbsp;mg/day in women with breast cancer.<ref name="pmid15755972">{{Cite journal |vauthors=Fabian CJ, Kimler BF |date=March 2005 |title=Selective estrogen-receptor modulators for primary prevention of breast cancer |journal=Journal of Clinical Oncology |volume=23 |issue=8 |pages=1644–1655 |doi=10.1200/JCO.2005.11.005 |pmid=15755972 |doi-access=free}}</ref> Tamoxifen has been found to decrease [[insulin-like growth factor 1]] (IGF-1) levels by 17 to 38% in women and men.<ref name="pmid27704479">{{Cite journal |vauthors=Duarte FH, Jallad RS, Bronstein MD |date=November 2016 |title=Estrogens and selective estrogen receptor modulators in acromegaly |journal=Endocrine |volume=54 |issue=2 |pages=306–314 |doi=10.1007/s12020-016-1118-z |pmid=27704479 |s2cid=10136018}}</ref> Suppression of IGF-1 production in the liver is a well-known action of estrogens and SERMs.<ref name="pmid27704479" /> A 10&nbsp;mg/day dosage of tamoxifen is nearly as effective as a 20&nbsp;mg/day dosage in suppressing IGF-1 levels.<ref name="MorelloWurz2003">{{Cite journal |vauthors=Morello KC, Wurz GT, DeGregorio MW |year=2003 |title=Pharmacokinetics of selective estrogen receptor modulators |journal=Clinical Pharmacokinetics |volume=42 |issue=4 |pages=361–372 |doi=10.2165/00003088-200342040-00004 |pmid=12648026 |s2cid=13003168}}</ref>

====Other activities====
Afimoxifene is an [[agonist]] of the [[G protein-coupled estrogen receptor]] (GPER) with relatively low [[affinity (pharmacology)|affinity]].<ref name="pmid26023144">{{Cite journal |vauthors=Prossnitz ER, Arterburn JB |date=July 2015 |title=International Union of Basic and Clinical Pharmacology. XCVII. G Protein-Coupled Estrogen Receptor and Its Pharmacologic Modulators |journal=Pharmacological Reviews |volume=67 |issue=3 |pages=505–540 |doi=10.1124/pr.114.009712 |pmc=4485017 |pmid=26023144}}</ref> Its affinity for the receptor is in the range of 100 to 1,000&nbsp;nM, relative to 3 to 6&nbsp;nM for estradiol.<ref name="pmid26023144" />

In addition to its activity as a SERM, afimoxifene binds to both the [[estrogen-related receptor β]] and [[estrogen-related receptor γ]] and is an antagonist of the [[estrogen-related receptor γ]] (ERRγ).<ref name="pmid16515477">{{Cite journal |vauthors=Ariazi EA, Jordan VC |date=2006 |title=Estrogen-related receptors as emerging targets in cancer and metabolic disorders |journal=Current Topics in Medicinal Chemistry |volume=6 |issue=3 |pages=203–215 |doi=10.2174/1568026610606030203 |pmid=16515477}}</ref>

[[Norendoxifen]] (4-hydroxy-''N'',''N''-didesmethyltamoxifen), another [[active metabolite]] of tamoxifen, has been found to act as a [[potency (pharmacology)|potent]] [[competitive inhibition|competitive]] [[aromatase inhibitor]] ([[IC50|IC<sub>50</sub>]] = 90&nbsp;nM), and may also be involved in the antiestrogenic activity of tamoxifen.<ref name="pmid23824607">{{Cite journal |vauthors=Liu J, Flockhart PJ, Lu D, Lv W, Lu WJ, Han X, Cushman M, Flockhart DA |date=September 2013 |title=Inhibition of cytochrome p450 enzymes by the e- and z-isomers of norendoxifen |journal=Drug Metabolism and Disposition |volume=41 |issue=9 |pages=1715–1720 |doi=10.1124/dmd.113.052506 |pmc=3876808 |pmid=23824607}}</ref>

In addition to its activity as a SERM, tamoxifen is a [[potency (pharmacology)|potent]] and [[binding selectivity|selective]] [[protein kinase C]] [[protein kinase inhibitor|inhibitor]], and is active in this regard at therapeutic concentrations.<ref name="ZarateManji2009">{{Cite journal |vauthors=Zarate CA, Manji HK |year=2009 |title=Protein kinase C inhibitors: rationale for use and potential in the treatment of bipolar disorder |journal=CNS Drugs |volume=23 |issue=7 |pages=569–582 |doi=10.2165/00023210-200923070-00003 |pmc=2802274 |pmid=19552485}}</ref> This action is thought to underlie the efficacy of tamoxifen in the treatment of [[bipolar disorder]].<ref name="ZarateManji2009" />

Tamoxifen is an inhibitor of [[P-glycoprotein]].<ref name="Nolvadex-Label" />

In 2018, it was discovered that tamoxifen directly interacts with the [[dopamine transporter]] (DAT) and acts as an atypical [[dopamine reuptake inhibitor]] (DRI).<ref name="NepalDasReith2023">{{Cite journal |vauthors=Nepal B, Das S, Reith ME, Kortagere S |date=2023 |title=Overview of the structure and function of the dopamine transporter and its protein interactions |journal=Front Physiol |volume=14 |pages=1150355 |doi=10.3389/fphys.2023.1150355 |pmc=10020207 |pmid=36935752 |doi-access=free}}</ref><ref name="MikelmanGuptaroySchmitt2018">{{Cite journal |vauthors=Mikelman SR, Guptaroy B, Schmitt KC, Jones KT, Zhen J, Reith ME, Gnegy ME |date=October 2018 |title=Tamoxifen Directly Interacts with the Dopamine Transporter |journal=J Pharmacol Exp Ther |volume=367 |issue=1 |pages=119–128 |doi=10.1124/jpet.118.248179 |pmc=7250473 |pmid=30108161}}</ref> It has weak [[potency (pharmacology)|potency]] (54% inhibition of dopamine uptake at 10{{nbsp}}μM) and lacks any [[psychostimulant|stimulant]] or [[central depressant|depressant]] effects when administered by itself.<ref name="NepalDasReith2023" /><ref name="MikelmanGuptaroySchmitt2018" /> However, tamoxifen [[dose dependence|dose-dependently]] blocks [[amphetamine]]-mediated [[dopamine releasing agent|dopamine release]] and psychostimulant-like effects in animals.<ref name="NepalDasReith2023" /><ref name="MikelmanGuptaroySchmitt2018" /> This unusual profile of DRI activity has made tamoxifen of potential interest as a starting point for [[structural modification]] to develop novel pharmaceutical drugs for treatment of [[stimulant use disorder]].<ref name="NepalDasReith2023" /><ref name="MikelmanGuptaroySchmitt2018" />

===Pharmacokinetics===

====Absorption====
Tamoxifen is rapidly and extensively [[absorption (pharmacokinetics)|absorbed]] from the [[intestine]]s with [[oral administration]].<ref name="MorelloWurz2003" /><ref name="BrennerStevens2017">{{Cite book |url=https://books.google.com/books?id=v3g4DwAAQBAJ&pg=PA394 |title=Brenner and Stevens' Pharmacology E-Book |vauthors=Brenner GM, Stevens C |date=28 September 2017 |publisher=Elsevier Health Sciences |isbn=978-0-323-39172-6 |pages=394–}}</ref> The [[oral administration|oral]] [[bioavailability]] of tamoxifen is approximately 100%, which is suggestive of minimal [[first-pass metabolism]] in the intestines and [[liver]].<ref name="MorelloWurz2003" /> Following intake, [[peak levels]] of tamoxifen occur after three to seven hours.<ref name="DeVitaLawrence2016" /><ref name="MorelloWurz2003" /> [[Steady state levels]] of tamoxifen are reached typically after 3 to 4&nbsp;weeks but possibly up to 16&nbsp;weeks of daily administration.<ref name="MorelloWurz2003" /><ref name="Nagar2010" /> Steady state levels of afimoxifene are achieved after 8&nbsp;weeks of daily tamoxifen administration.<ref name="Nagar2010">{{Cite book |title=Chemo Fog |vauthors=Nagar S |year=2010 |isbn=978-1-4419-6305-5 |series=Advances in Experimental Medicine and Biology |volume=678 |pages=124–132 |chapter=Pharmacokinetics of Anti-Cancer Drugs Used in Breast Cancer Chemotherapy |doi=10.1007/978-1-4419-6306-2_16 |pmid=20738014 |s2cid=12537667}}</ref><ref name="ChabnerLongo2011">{{Cite book |url=https://books.google.com/books?id=0U4aj4GZWCIC&pg=PA655 |title=Cancer Chemotherapy and Biotherapy: Principles and Practice |vauthors=Chabner BA, Longo DL |date=7 December 2011 |publisher=Lippincott Williams & Wilkins |isbn=978-1-4511-4820-6 |pages=655–}}</ref> Peak levels of tamoxifen after a single 40&nbsp;mg oral dose were 65&nbsp;ng/mL and steady state levels at 20&nbsp;mg/day were 310&nbsp;ng/mL.<ref name="MorelloWurz2003" /> Levels of tamoxifen show clear [[dose dependency]] across a dosage range of 1 to 20&nbsp;mg/day.<ref name="MorelloWurz2003" /><ref name="pmid15073109">{{Cite journal |vauthors=Kisanga ER, Gjerde J, Guerrieri-Gonzaga A, Pigatto F, Pesci-Feltri A, Robertson C, Serrano D, Pelosi G, Decensi A, Lien EA |date=April 2004 |title=Tamoxifen and metabolite concentrations in serum and breast cancer tissue during three dose regimens in a randomized preoperative trial |journal=Clinical Cancer Research |volume=10 |issue=7 |pages=2336–2343 |doi=10.1158/1078-0432.ccr-03-0538 |pmid=15073109 |doi-access=free}}</ref> Endoxifen levels are approximately 5 to 10 times higher than afimoxifene levels, with large [[interindividual variability]].<ref name="Sanchez-SpitmanSwen2019" /><ref name="pmid23962908" /> Endoxifen levels have been reported as 10.8 to 15.9&nbsp;ng/mL at steady state in [[CYP2D6]] normal metabolizers during therapy with 20&nbsp;mg/day tamoxifen.<ref name="Sanchez-SpitmanSwen2019" /> The most abundant [[metabolite]]s of tamoxifen in terms of circulating concentrations are [[N-desmethyltamoxifen|''N''-desmethyltamoxifen]], [[N,N-didesmethyltamoxifen|''N'',''N''-didesmethyltamoxifen]], [[endoxifen|(''Z'')-endoxifen]], and tamoxifen ''N''-oxide.<ref name="pmid21451508">{{Cite journal |vauthors=Mürdter TE, Schroth W, Bacchus-Gerybadze L, Winter S, Heinkele G, Simon W, Fasching PA, Fehm T, Eichelbaum M, Schwab M, Brauch H |date=May 2011 |title=Activity levels of tamoxifen metabolites at the estrogen receptor and the impact of genetic polymorphisms of phase I and II enzymes on their concentration levels in plasma |journal=Clinical Pharmacology and Therapeutics |volume=89 |issue=5 |pages=708–717 |doi=10.1038/clpt.2011.27 |pmid=21451508 |s2cid=20082053}}</ref><ref name="pmid6184101">{{Cite journal |vauthors=Jordan VC |date=1982 |title=Metabolites of tamoxifen in animals and man: identification, pharmacology, and significance |journal=Breast Cancer Research and Treatment |volume=2 |issue=2 |pages=123–138 |doi=10.1007/BF01806449 |pmid=6184101 |s2cid=25119313}}</ref>

====Distribution====
The [[volume of distribution]] of tamoxifen is 50 to 60&nbsp;L/kg and its [[clearance (pharmacology)|clearance]] has been estimated as 1.2 to 5.1&nbsp;L/hour.<ref name="MorelloWurz2003" /><ref name="DeVitaLawrence2016">{{Cite book |url=https://books.google.com/books?id=Bf3DCwAAQBAJ&pg=PT990 |title=Prostate and Other Genitourinary Cancers: From Cancer: Principles & Practice of Oncology, 10th edition |vauthors=DeVita VT, Lawrence TS, Rosenberg SA |author-link2=Theodore S. Lawrence |date=18 March 2016 |publisher=Wolters Kluwer Health |isbn=978-1-4963-5421-1 |pages=990–}}</ref> High concentrations of tamoxifen have been found in [[breast]], [[uterus]], liver, [[kidney]], [[lung]], [[pancreas]], and [[ovary]] tissue in animals and humans.<ref name="MorelloWurz2003" /> Levels of tamoxifen in the uterus have been found to be 2- to 3-fold higher than in the circulation<ref name="MorelloWurz2003" /> and in the breasts 10-fold higher than in the circulation.<ref name="pmid15073109" /> The [[plasma protein binding]] of tamoxifen and afimoxifene is greater than 99%.<ref name="ChabnerLongo2011" /> A majority of tamoxifen is bound to [[human serum albumin|albumin]].<ref name="MorelloWurz2003" /> Albumin alone binds 98.8% of tamoxifen while other [[plasma protein]]s are not greatly involved.<ref name="pmid2702659">{{Cite journal |vauthors=Lien EA, Solheim E, Lea OA, Lundgren S, Kvinnsland S, Ueland PM |date=April 1989 |title=Distribution of 4-hydroxy-N-desmethyltamoxifen and other tamoxifen metabolites in human biological fluids during tamoxifen treatment |url=https://cancerres.aacrjournals.org/content/49/8/2175.short |journal=Cancer Research |volume=49 |issue=8 |pages=2175–2183 |pmid=2702659}}</ref>

====Metabolism====
{| class="wikitable floatright"
|+Tamoxifen and its metabolites in humans<ref name="pmid19574470">{{Cite journal |vauthors=Brauch H, Mürdter TE, Eichelbaum M, Schwab M |date=October 2009 |title=Pharmacogenomics of tamoxifen therapy |journal=Clinical Chemistry |volume=55 |issue=10 |pages=1770–1782 |doi=10.1373/clinchem.2008.121756 |pmid=19574470 |doi-access=free}}</ref>
!Compound
!Mean plasma<br />concentrations
!Effect on ER / affinity for ER<sup>a</sup>
|-
|Tamoxifen
|190–420 nmol/L
|Weak antagonist / 2%
|-
|[[N-Desmethyltamoxifen|''N''-Desmethyltamoxifen]]
|280–800 nmol/L
|Weak antagonist / 1%
|-
|[[N,N-Desmethyltamoxifen|''N'',''N''-Desmethyltamoxifen]]
|90–120 nmol/L
|Weak antagonist
|-
|[[Endoxifen]]
|14–130 nmol/L
|Strong antagonist / equal to afimoxifene
|-
|[[Afimoxifene]]
|3–17 nmol/L<sup>b</sup>
|Strong antagonist / 188%
|-
|α-Hydroxytamoxifen
|1 nmol/L
|None
|-
|3,4-Dihydroxytamoxifen
|?
|Weak antagonist / high affinity
|-
|Tamoxifen ''N''-oxide
|15–24 nmol/L
|Weak antagonist<sup>c</sup>
|-
| colspan="3" style="width: 1px; background-color:#eaecf0; text-align: center;" | '''Footnotes:''' <sup>a</sup> = Estradiol is 100%. <sup>b</sup> = One study reported a much higher concentration (67 nmol/L). <sup>c</sup> = Might be due to reduction to tamoxifen.
|}

Tamoxifen is a [[prodrug]] and is [[metabolism|metabolized]] in the [[liver]] by the [[cytochrome P450]] [[isoform]]s [[CYP3A4]], [[CYP2C9]], and [[CYP2D6]] into [[active metabolite]]s such as [[endoxifen]] (4-hydroxy-''N''-desmethyltamoxifen) and [[afimoxifene]] (4-hydroxytamoxifen).<ref name="MorelloWurz2003" /><ref name="Nolvadex-Label" /><ref name="Sanchez-SpitmanSwen2019">{{Cite journal |vauthors=Sanchez-Spitman AB, Swen JJ, Dezentje VO, Moes DJ, Gelderblom H, Guchelaar HJ |date=June 2019 |title=Clinical pharmacokinetics and pharmacogenetics of tamoxifen and endoxifen |journal=Expert Review of Clinical Pharmacology |volume=12 |issue=6 |pages=523–536 |doi=10.1080/17512433.2019.1610390 |pmid=31008668 |doi-access=free}}</ref> Conversion of tamoxifen by ''N''-demethylation into [[N-desmethyltamoxifen|''N''-desmethyltamoxifen]], which is catalyzed primarily by CYP3A4 and [[CYP3A5]], is responsible for approximately 92% of tamoxifen metabolism.<ref name="pmid23962908">{{Cite journal |vauthors=Klein DJ, Thorn CF, Desta Z, Flockhart DA, Altman RB, Klein TE |date=November 2013 |title=PharmGKB summary: tamoxifen pathway, pharmacokinetics |journal=Pharmacogenetics and Genomics |volume=23 |issue=11 |pages=643–647 |doi=10.1097/FPC.0b013e3283656bc1 |pmc=4084801 |pmid=23962908}}</ref> Conversely, 4-hydroxylation of tamoxifen into afimoxifene is responsible for only about 7% of tamoxifen metabolism.<ref name="pmid23962908" /> Following its formation, ''N''-desmethyltamoxifen is [[oxidation|oxidized]] into several other metabolites, the most notable of which is endoxifen.<ref name="pmid23962908" /> Another active metabolite, [[norendoxifen]] (4-hydroxy-''N'',''N''-didesmethyltamoxifen), is formed via ''N''-demethylation of endoxifen or 4-hydroxylation of [[N,N-didesmethyltamoxifen|''N'',''N''-didesmethyltamoxifen]].<ref name="Sanchez-SpitmanSwen2019" /> Tamoxifen and its metabolites undergo [[conjugation (biochemistry)|conjugation]], including [[glucuronidation]] and [[sulfation]].<ref name="Nagar2010" /> Tamoxifen may inhibit its own metabolism.<ref name="MorelloWurz2003" />

====Elimination====
Tamoxifen has a long [[elimination half-life]] of typically 5 to 7&nbsp;days, with a range of 4 to 11&nbsp;days.<ref name="MorelloWurz2003" /><ref name="Sanchez-SpitmanSwen2019" /><ref name="DeVitaLawrence2016" /> Similarly, the half-life of afimoxifene is 14&nbsp;days.<ref name="ChabnerLongo2011" /> Conversely, the half-life of [[endoxifen]] is 50 to 70&nbsp;hours (2–3&nbsp;days).<ref name="Sanchez-SpitmanSwen2019" /> The long half-lives of tamoxifen and afimoxifene are attributed to their high plasma protein binding as well as to [[enterohepatic recirculation]].<ref name="ChabnerLongo2011" /> Upon discontinuation of treatment, levels of tamoxifen and its metabolites persist in the circulation for at least 6&nbsp;weeks.<ref name="ChabnerLongo2011" /> Tamoxifen is [[excretion|excreted]] in [[bile]] and is [[elimination (pharmacology)|eliminated]] in [[feces]], while small amounts are eliminated in [[urine]].<ref name="MorelloWurz2003" />

==Chemistry==
Tamoxifen is a [[nonsteroidal]] SERM of the [[triphenylethylene]] family and was structurally derived from [[diethylstilbestrol]]-like estrogens and [[antiestrogen]]s such as [[chlorotrianisene]] and [[ethamoxytriphetol]].<ref name="Jordan1986">{{Cite book |url=https://books.google.com/books?id=7WmLZfGXST0C&pg=PA28 |title=Estrogen/antiestrogen Action and Breast Cancer Therapy |vauthors=Jordan VC |publisher=Univ of Wisconsin Press |year=1986 |isbn=978-0-299-10480-1 |pages=28,154}}</ref><ref name="Pratt1994">{{Cite book |url=https://books.google.com/books?id=nPR1L4K5HuEC&pg=PA21 |title=The Anticancer Drugs |vauthors=Pratt WB |publisher=Oxford University Press |year=1994 |isbn=978-0-19-506739-2 |pages=21–}}</ref><ref name="MaximovMcDaniel2013">{{Cite book |url=https://books.google.com/books?id=p-W5BAAAQBAJ&pg=PA7 |title=Tamoxifen: Pioneering Medicine in Breast Cancer |vauthors=Maximov PY, McDaniel RE, Jordan VC |date=23 July 2013 |publisher=Springer Science & Business Media |isbn=978-3-0348-0664-0 |pages=7–}}</ref><ref name="Ravina2011">{{Cite book |url=https://books.google.com/books?id=iDNy0XxGqT8C&pg=PA177 |title=The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs |vauthors=Ravina E |date=11 January 2011 |publisher=John Wiley & Sons |isbn=978-3-527-32669-3 |pages=177–178}}</ref> Initially, [[clomifene]] was synthesized, and tamoxifen was developed subsequently.<ref name="Jordan1986" /><ref name="MaximovMcDaniel2013" /><ref name="Ravina2011" /> Tamoxifen is closely related structurally to other triphenylethylenes, such as clomifene, [[nafoxidine]], [[ospemifene]], [[toremifene]], and numerous others.<ref name="CanoAlsina2006">{{Cite book |url=https://books.google.com/books?id=heJDAAAAQBAJ&pg=PA52 |title=Selective Estrogen Receptor Modulators: A New Brand of Multitarget Drugs |vauthors=Cano A, Calaf i Alsina J, Duenas-Diez JL |date=22 September 2006 |publisher=Springer Science & Business Media |isbn=978-3-540-34742-2 |pages=52–}}</ref><ref name="OrwollBilezikian2009">{{Cite book |url=https://books.google.com/books?id=nfWNYFdOsCsC&pg=PA717 |title=Osteoporosis in Men: The Effects of Gender on Skeletal Health |vauthors=Orwoll ES, Bilezikian JP, Vanderschueren D |date=30 November 2009 |publisher=Academic Press |isbn=978-0-08-092346-8 |pages=717–}}</ref> Other SERMs, like [[raloxifene]], are structurally distinct from tamoxifen and other triphenylethylenes.<ref name="OrwollBilezikian2009" />

==History==
In the late 1950s, pharmaceutical companies were actively researching a newly discovered class of anti-estrogen compounds in the hope of developing a morning-after contraceptive pill. Arthur L Walpole was a reproductive [[endocrinologist]] who led such a team at the [[Alderley Park]] research laboratories of [[Imperial Chemical Industries|ICI]] Pharmaceuticals.<ref name="Jordan_2006" /> It was there in 1962 that chemist Dora Richardson first synthesized tamoxifen, back then known as ICI-46,474, when she was looking to create triphenylethylene derivatives for the contraceptive pill project that her team was researching.<ref name="isbn0-471-89979-8">{{Cite book |title=Drug Discovery: A History |vauthors=Sneader W |publisher=Wiley |year=2005 |isbn=978-0-471-89979-2 |location=New York |page=472 pages}}</ref>

This compound was originally created to work as an estrogen inhibitor, but instead was found to stimulate ovulation in participants of the drug testing trial.<ref name="Viviane M 2017">{{Cite journal |vauthors=Quirke VM |date=12 September 2017 |title=Tamoxifen from Failed Contraceptive Pill to Best-Selling Breast Cancer Medicine: A Case-Study in Pharmaceutical Innovation |journal=Frontiers in Pharmacology |volume=8 |pages=620 |doi=10.3389/fphar.2017.00620 |pmc=5600945 |pmid=28955226 |doi-access=free}}</ref> Walpole and his colleagues filed a UK patent covering this compound in 1962, but patent protection on this compound was repeatedly denied in the US until the 1980s.<ref name="Jordan_2003">{{Cite journal |vauthors=Jordan VC |date=March 2003 |title=Tamoxifen: a most unlikely pioneering medicine |journal=Nature Reviews. Drug Discovery |volume=2 |issue=3 |pages=205–213 |doi=10.1038/nrd1031 |pmid=12612646 |s2cid=31333174}}</ref> Tamoxifen did eventually receive marketing approval as a fertility treatment, but the class of compounds never proved useful in human contraception. A link between estrogen and breast cancer had been known for many years, but cancer treatments were not a corporate priority at the time, and Walpole's personal interests were important in keeping support for the compound alive in the face of this and the lack of patent protection.<ref name="Jordan_2006" /> It was only when Walpole threatened to leave his position that corporate decided to allow trials and testing for tamoxifen as a drug that could be used to treat breast cancer. Without Walpole's effort towards defending the work that his team had done in discovering a possibly revolutionary source for breast cancer treatment, tamoxifen could have become a discarded or under-researched idea. Walpole's team consisted of Dora Richardson and G. A. Snow, who worked on the chemistry portion of the project, along with G. E. Paget and J. K. Walley, who focused primarily on the biological side.<ref name="Viviane M 2017" />

Tamoxifen is one of three drugs in an [[angiogenesis inhibitor|anti-angiogenetic]] protocol developed by [[Judah Folkman|Dr. Judah Folkman]], a researcher at Children's Hospital at Harvard Medical School in Boston. Folkman discovered in the 1970s that [[angiogenesis]] – the growth of new blood vessels – plays a significant role in the development of cancer. Since his discovery, an entirely new field of cancer research has developed. Clinical trials on [[angiogenesis inhibitor]]s have been underway since 1992 using many different drugs. The Harvard researchers developed a specific protocol for a golden retriever named Navy who was cancer-free after receiving the prescribed cocktail of [[celecoxib]], [[doxycycline]], and tamoxifen – the treatment subsequently became known as the Navy Protocol.<ref name="urlUSA_Today">{{Cite web |date=24 July 2002 |title=Dog's tale of survival opens door in cancer research |url=https://www.usatoday.com/news/health/2002-07-24-cover-cancer_x.htm |url-status=live |archive-url=https://web.archive.org/web/20080628110635/http://www.usatoday.com/news/health/2002-07-24-cover-cancer_x.htm |archive-date=28 June 2008 |access-date=24 June 2008 |website=Health and Behavior |publisher=USA Today |vauthors=Kirk E}}</ref> Furthermore, tamoxifen treatment alone has been shown to have anti-angiogenetic effects in animal models of cancer which appear to be, at least in part, independent of tamoxifen's ER antagonist properties.<ref name="pmid11106254">{{Cite journal |author-link7=Mark Dewhirst |vauthors=Blackwell KL, Haroon ZA, Shan S, Saito W, Broadwater G, Greenberg CS, Dewhirst MW |date=November 2000 |title=Tamoxifen inhibits angiogenesis in estrogen receptor-negative animal models |url=http://clincancerres.aacrjournals.org/cgi/content/abstract/6/11/4359 |url-status=live |journal=Clinical Cancer Research |volume=6 |issue=11 |pages=4359–4364 |pmid=11106254 |archive-url=https://web.archive.org/web/20080906195254/http://clincancerres.aacrjournals.org/cgi/content/abstract/6/11/4359 |archive-date=6 September 2008}}</ref>

Other antiestrogens, such as [[ethamoxytriphetol]] (MER-25) and [[clomifene]] (MRL-41), were assessed for treatment of breast cancer and found to be effective before tamoxifen, but were plagued with [[toxicity]] issues.<ref name="pmid12796359"/><ref name="HowellJordan2013B">{{Cite book |title=Estrogen Action, Selective Estrogen Receptor Modulators And Women's Health: Progress And Promise |vauthors=Howell A, Jordan VC |publisher=World Scientific |year=2013 |isbn=978-1-84816-959-3 |veditors=Jordon VC |pages=229–254 |chapter=Adjuvant Antihormone Therapy |doi=10.1142/9781848169586_0010 |chapter-url=https://books.google.com/books?id=ZM26CgAAQBAJ&pg=PA229}}</ref> The first clinical study of tamoxifen took place at the [[Christie Hospital]] in 1971, and showed a convincing effect in advanced breast cancer, but nevertheless ICI's development programme came close to termination when it was reviewed in 1972.<ref name="Cole_1971">{{Cite journal |vauthors=Cole MP, Jones CT, Todd ID |date=June 1971 |title=A new anti-oestrogenic agent in late breast cancer. An early clinical appraisal of ICI46474 |journal=British Journal of Cancer |volume=25 |issue=2 |pages=270–275 |doi=10.1038/bjc.1971.33 |pmc=2008453 |pmid=5115829}}</ref> In an unpublished article from the early days of the trial, Dora Richardson documented her team's excitement about tamoxifen's effects in counteracting infertility problems and the early positive effects found in breast cancer patients. Unfortunately, this work was not well received by everyone, as the team was supposed to be looking for a contraceptive pill.<ref name="Viviane M 2017" /> Tamoxifen's further development may have been bolstered by a second clinical study by Harold W.C. Ward <ref name="Ward_1973">{{Cite journal |vauthors=Ward HW |date=January 1973 |title=Anti-oestrogen therapy for breast cancer: a trial of tamoxifen at two dose levels |journal=British Medical Journal |volume=1 |issue=5844 |pages=13–14 |doi=10.1136/bmj.1.5844.13 |pmc=1588574 |pmid=4567104}}</ref> at the [[Queen Elizabeth Hospital Birmingham|Queen Elizabeth Hospital, Birmingham]]. Ward's study showed a more definitive response to the drug at a higher dosage. Walpole also may have helped to convince the company to market tamoxifen for late stage breast cancer in 1973.<ref name="Jordan_2003" /> He was also instrumental in funding [[V. Craig Jordan]] to work on tamoxifen. In 1972, ICI Pharmaceuticals Division abandoned development of tamoxifen for financial reasons. The drug was subsequently reinvented from a failed contraceptive, to become tamoxifen, the gold standard for the adjuvant treatment of breast cancer and the pioneering medicine for chemprevention for high-risk women.<ref>{{Cite web |title=Maverick and pioneer whose work is improving odds in breast cancer fight |url=http://www.yorkshirepost.co.uk/news/features/maverick-and-pioneer-whose-work-is-improving-odds-in-breast-cancer-fight-1-5799838 |url-status=live |archive-url=https://web.archive.org/web/20130628015824/http://www.yorkshirepost.co.uk/news/features/maverick-and-pioneer-whose-work-is-improving-odds-in-breast-cancer-fight-1-5799838 |archive-date=28 June 2013 |access-date=5 November 2013}}</ref><ref>{{Cite news |date=27 June 2013 |title=Maverick and pioneer whose work is improving odds in breast cancer fight |url=http://www.yorkshirepost.co.uk/news/analysis/maverick-and-pioneer-whose-work-is-improving-odds-in-breast-cancer-fight-1-5799838 |url-status=live |archive-url=https://web.archive.org/web/20160309182447/http://www.yorkshirepost.co.uk/news/analysis/maverick-and-pioneer-whose-work-is-improving-odds-in-breast-cancer-fight-1-5799838 |archive-date=9 March 2016 |access-date=7 April 2017 |work=The Yorkshire Post}}</ref> Two books, ''Estrogen Action, Selective Estrogen Receptor Modulators and Women's Health'' (Imperial College Press 2013) and ''Tamoxifen: Pioneering Medicine in Breast Cancer'' (Springer 2013) tell this story.

{{Comparison of early clinical experience with antiestrogens for advanced breast cancer}}

1980 saw the publication of the first trial to show that tamoxifen given in addition to chemotherapy improved survival for patients with early breast cancer.<ref name="Baum_2003">{{Cite journal |vauthors=Baum M, Brinkley DM, Dossett JA, McPherson K, Patterson JS, Rubens RD, Smiddy FG, Stoll BA, Wilson A, Lea JC, Richards D, Ellis SH |date=August 1983 |title=Improved survival among patients treated with adjuvant tamoxifen after mastectomy for early breast cancer |journal=Lancet |volume=2 |issue=8347 |pages=450 |doi=10.1016/S0140-6736(83)90406-3 |pmid=6135926 |s2cid=54230182}}</ref> In advanced disease, tamoxifen is now only recognized as effective in ER+ patients, but the early trials did not select ER+ patients, and by the mid-1980s the clinical trial picture was not showing a major advantage for tamoxifen.<ref name="FURR_1984">{{Cite journal |vauthors=Furr BJ, Jordan VC |year=1984 |title=The pharmacology and clinical uses of tamoxifen |journal=Pharmacology & Therapeutics |volume=25 |issue=2 |pages=127–205 |doi=10.1016/0163-7258(84)90043-3 |pmid=6438654}}</ref> Nevertheless, tamoxifen had a relatively mild side-effect profile, and a number of large trials continued.{{cn|date=January 2025}}

The pharmacology of SERMs was discovered, defined, and deciphered during the 1980s.<ref>{{Cite journal |vauthors=Jordan VC |date=August 2001 |title=Selective estrogen receptor modulation: a personal perspective |journal=Cancer Research |volume=61 |issue=15 |pages=5683–5687 |pmid=11479197}}</ref> A clinical strategy was described<ref>{{Cite journal |vauthors=Lerner LJ, Jordan VC |date=July 1990 |title=Development of antiestrogens and their use in breast cancer: eighth Cain memorial award lecture |journal=Cancer Research |volume=50 |issue=14 |pages=4177–4189 |pmid=2194650}}</ref> that led to the creation of SERMs as a group of multifunctional medicines aimed at the treatment or prevention of many conditions in postmenopausal women, e.g. osteoporosis and breast cancer.<ref>{{Cite book |last=V Craig |first=Jordan |url=https://www.worldscientific.com/worldscibooks/10.1142/p868 |title=Estrogen Action, Selective Estrogen Receptor Modulators and Women's Health |date=July 2013 |publisher=Imperial College Press |isbn=978-1-84816-958-6 |doi=10.1142/p868 |access-date=17 November 2024}}</ref>

The early sales of tamoxifen in both the UK and in the U.S. far exceeded ICI's original estimate, but despite this, at the annual portfolio review ICI's board members still asserted that "there was no market for cancer", leaving the drug's marketing success to rely on its clinical results and clinicians' and scientists' interests in it. Shortly after, Dora Richardson published a history of tamoxifen that, unusually for that type of paper, included personal accounts and letters from patients who attributed their healing to the drug. This testimony from cancer patients using tamoxifen helped to shape and push forward research, by justifying it both morally and scientifically to corporations.<ref name="Viviane M 2017" />

It was not until 1998 that the meta-analysis of the Oxford-based Early Breast Cancer Trialists' Collaborative Group showed definitively that tamoxifen was effective for early breast cancer.<ref name="pmid9605801">{{Cite journal |last=Early Breast Cancer Trialists' Collaborative Group |date=May 1998 |title=Tamoxifen for early breast cancer: an overview of the randomised trials. |journal=Lancet |volume=351 |issue=9114 |pages=1451–1467 |doi=10.1016/S0140-6736(97)11423-4 |pmid=9605801 |s2cid=46287542}}</ref>

==Society and culture==

===Brand names===
Tamoxifen is marketed under the brand names Nolvadex and Soltamox, and a variety of other brand names throughout the world.<ref name="drug dictionary" /><ref name="Drugs.com">{{Cite web |title=Tamoxifen |url=https://www.drugs.com/international/tamoxifen.html}}</ref>

===Economics===
Global sales of tamoxifen in 2001 were approximately $1.02 billion.<ref name="urlCancer the generic impact">{{Cite web |title=Cancer the generic impact |url=http://www.bioportfolio.com/news/datamonitor_16.htm |url-status=dead |archive-url=https://web.archive.org/web/20080516032316/http://www.bioportfolio.com/news/datamonitor_16.htm |archive-date=16 May 2008 |access-date=14 November 2008 |publisher=BioPortfolio Limited}}</ref> Since the expiration of the patent in 2002, it is widely available as a [[generic drug]] around the world. {{As of|2004}}, tamoxifen was the world's largest selling hormonal drug for the treatment of breast cancer.<ref name="urlwww.astrazeneca.se">{{Cite web |title=AstraZenecain Cancer: Slide #15 |url=http://www.astrazeneca.com/_mshost3690701/content/resources/media/investors/2004-abr-brent-vose-oncology.pdf |url-status=live |archive-url=https://web.archive.org/web/20100131160325/http://astrazeneca.com/_mshost3690701/content/resources/media/investors/2004-abr-brent-vose-oncology.pdf |archive-date=31 January 2010 |access-date=28 March 2009 |website=AstraZeneca Annual Business Review |publisher=www.astrazeneca.com |quote=2004 tamoxifen market share: 70% Source: IMS HEALTH, IMS MIDAS Monthly. July 2004. Aromatase Inhibitors + Tamoxifen |vauthors=Vose B}}</ref>

==Research==
In [[McCune-Albright syndrome]] (MAS) tamoxifen has been used to treat [[premature puberty]] and the consequences of premature puberty. Tamoxifen has been seen to decrease rapid [[bone maturation]] which is the result of [[Hyperestrogenism|excessive estrogen]] and alter predicted adult height (PAH).<ref>{{Cite journal |vauthors=Eugster EA, Shankar R, Feezle LK, Pescovitz OH |year=1999 |title=Tamoxifen treatment of progressive precocious puberty in a patient with McCune-Albright syndrome |journal=Journal of Pediatric Endocrinology & Metabolism |volume=12 |issue=5 |pages=681–686 |doi=10.1515/jpem.1999.12.5.681 |pmid=10703542 |s2cid=71034635}}</ref><ref>{{Cite journal |vauthors=Eugster EA, Rubin SD, Reiter EO, Plourde P, Jou HC, Pescovitz OH |date=July 2003 |title=Tamoxifen treatment for precocious puberty in McCune-Albright syndrome: a multicenter trial |journal=The Journal of Pediatrics |volume=143 |issue=1 |pages=60–66 |doi=10.1016/S0022-3476(03)00128-8 |pmid=12915825}}</ref> The same effects have also been seen in short pubertal boys.<ref>{{Cite journal |vauthors=Kreher NC, Eugster EA, Shankar RR |date=December 2005 |title=The use of tamoxifen to improve height potential in short pubertal boys |journal=Pediatrics |volume=116 |issue=6 |pages=1513–1515 |doi=10.1542/peds.2005-0577 |pmid=16322179 |s2cid=45133251}}</ref> However, one ''in vitro'' study in 2007 and later an ''in vivo'' study in 2008 have shown that tamoxifen induces apoptosis in growth plate chondrocytes, reduces serum [[insulin-like growth factor 1]] (IGF-1) levels and causes persistent retardation of longitudinal and cortical radial bone growth in young male rats, leading the researchers to express concern giving tamoxifen to growing individuals.<ref name="pmid18348701">{{Cite journal |vauthors=Karimian E, Chagin AS, Gjerde J, Heino T, Lien EA, Ohlsson C, Sävendahl L |date=August 2008 |title=Tamoxifen impairs both longitudinal and cortical bone growth in young male rats |journal=Journal of Bone and Mineral Research |volume=23 |issue=8 |pages=1267–1277 |doi=10.1359/jbmr.080319 |pmid=18348701 |s2cid=35813153 |doi-access=free}}</ref><ref>{{Cite journal |vauthors=Chagin AS, Karimian E, Zaman F, Takigawa M, Chrysis D, Sävendahl L |date=May 2007 |title=Tamoxifen induces permanent growth arrest through selective induction of apoptosis in growth plate chondrocytes in cultured rat metatarsal bones |journal=Bone |volume=40 |issue=5 |pages=1415–1424 |doi=10.1016/j.bone.2006.12.066 |pmid=17293177}}</ref>

Tamoxifen has been studied in the treatment of the rare conditions of [[retroperitoneal fibrosis]]<ref name="pmid16418409">{{Cite journal |vauthors=van Bommel EF, Hendriksz TR, Huiskes AW, Zeegers AG |date=January 2006 |title=Brief communication: tamoxifen therapy for nonmalignant retroperitoneal fibrosis |journal=Annals of Internal Medicine |volume=144 |issue=2 |pages=101–106 |doi=10.7326/0003-4819-144-2-200601170-00007 |pmid=16418409 |s2cid=25699557}}</ref> and [[idiopathic sclerosing mesenteritis]].<ref name="pmid17478346">{{Cite journal |vauthors=Akram S, Pardi DS, Schaffner JA, Smyrk TC |date=May 2007 |title=Sclerosing mesenteritis: clinical features, treatment, and outcome in ninety-two patients |journal=Clinical Gastroenterology and Hepatology |volume=5 |issue=5 |pages=589–96; quiz 523–4 |doi=10.1016/j.cgh.2007.02.032 |pmid=17478346 |doi-access=free}}</ref> It has also been proposed as part of a treatment plan for [[Riedel's thyroiditis]].<ref name="pmid12698518">{{Cite journal |vauthors=Dabelic N, Jukic T, Labar Z, Novosel SA, Matesa N, Kusic Z |date=April 2003 |title=Riedel's thyroiditis treated with tamoxifen |url=http://www.cmj.hr/2003/44/2/12698518.pdf |url-status=live |journal=Croatian Medical Journal |volume=44 |issue=2 |pages=239–241 |pmid=12698518 |archive-url=https://web.archive.org/web/20080910130853/http://www.cmj.hr/2003/44/2/12698518.pdf |archive-date=10 September 2008}}</ref>

Tamoxifen is used as a research tool to trigger tissue-specific gene expression in many conditional expression constructs in [[genetically modified animal]]s including a version of the [[Cre-Lox recombination]] technique.<ref name="pmid8855277">{{Cite journal |vauthors=Feil R, Brocard J, Mascrez B, LeMeur M, Metzger D, Chambon P |date=October 1996 |title=Ligand-activated site-specific recombination in mice |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=93 |issue=20 |pages=10887–10890 |bibcode=1996PNAS...9310887F |doi=10.1073/pnas.93.20.10887 |pmc=38252 |pmid=8855277 |doi-access=free}}</ref> While widely used in transgenic research, the strong anabolic effect of tamoxifen on bone might confound this approach, especially as it relates to bone-targeted constructs.

Tamoxifen may be effective in the treatment of [[mania]] in people with [[bipolar disorder]].<ref name="TalaeiPourgholami2016">{{Cite journal |vauthors=Talaei A, Pourgholami M, Khatibi-Moghadam H, Faridhosseini F, Farhoudi F, Askari-Noghani A, Sadeghi R |date=June 2016 |title=Tamoxifen: A Protein Kinase C Inhibitor to Treat Mania: A Systematic Review and Meta-Analysis of Randomized, Placebo-Controlled Trials |journal=Journal of Clinical Psychopharmacology |volume=36 |issue=3 |pages=272–275 |doi=10.1097/JCP.0000000000000492 |pmid=27088436 |s2cid=39792641}}</ref> This is thought to be due to blockade of [[protein kinase C]] (PKC), an [[enzyme]] that regulates [[neuron]] activity in the [[brain]].<ref name="TalaeiPourgholami2016" /><ref name="SaxenaScaini2017">{{Cite journal |vauthors=Saxena A, Scaini G, Bavaresco DV, Leite C, Valvassori SS, Carvalho AF, Quevedo J |date=November 2017 |title=Role of Protein Kinase C in Bipolar Disorder: A Review of the Current Literature |journal=Molecular Neuropsychiatry |volume=3 |issue=2 |pages=108–124 |doi=10.1159/000480349 |pmc=5701269 |pmid=29230399}}</ref> Researchers believe PKC is overactive during the mania in bipolar patients.<ref name="TalaeiPourgholami2016" /><ref name="SaxenaScaini2017" /> {{As of|September 2019}}, [[endoxifen]], a major active metabolite of tamoxifen with a 4-fold more potent PKC inhibition, was in [[Phases of clinical research#Phase III|phase III]] clinical trials for bipolar disorder.<ref name="AdisInsight-Endoxifen">{{Cite web |title=Endoxifen - Intas Pharmaceuticals/Jina pharmaceuticals |url=https://adisinsight.springer.com/drugs/800036114 |website=AdisInsight |publisher=Springer Nature Switzerland AG}}</ref><ref name="pmid29207335">{{Cite journal |vauthors=Ahmad I |date=January 2018 |title=Tamoxifen a pioneering drug: An update on the therapeutic potential of tamoxifen derivatives |journal=European Journal of Medicinal Chemistry |volume=143 |pages=515–531 |doi=10.1016/j.ejmech.2017.11.056 |pmid=29207335}}</ref>

== References ==
{{Reflist}}

== Further reading ==
* {{Cite book |url=https://www.ncbi.nlm.nih.gov/books/NBK61999/ |title=Medical Genetics Summaries |vauthors=Dean L |publisher=[[National Center for Biotechnology Information]] (NCBI) |year=2014 |veditors=Pratt VM, McLeod HL, Rubinstein WS, Scott SA, Dean LC, Kattman BL, Malheiro AJ |chapter=Tamoxifen Therapy and CYP2D6 Genotype |pmid=28520357 |id=Bookshelf ID: NBK247013 |display-editors=3 |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK247013/}}

== External links ==
* {{Cite web |date=5 October 2006 |title=Tamoxifen citrate |url=https://www.cancer.gov/about-cancer/treatment/drugs/tamoxifencitrate |website=National Cancer Institute}}

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