Array ( [0] => {{Short description|Medication}} [1] => {{Use dmy dates|date=October 2022}} [2] => {{Drugbox [3] => | Watchedfields = changed [4] => | verifiedrevid = 470477095 [5] => | image = Tamoxifen2DACS.svg [6] => | width = 250 [7] => | alt = [8] => | image2 = Tamoxifen-3D-balls.png [9] => | width2 = 175 [10] => | alt2 = [11] => [12] => [13] => | tradename = Nolvadex, Genox, Tamifen, others{{cite web|title=NCI Drug Dictionary|url=https://www.cancer.gov/publications/dictionaries/cancer-drug/def/tamoxifen-citrate |access-date=12 September 2021|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|date = 2 February 2011}} [14] => | Drugs.com = {{drugs.com|monograph|tamoxifen-citrate}} [15] => | MedlinePlus = a682414 [16] => | DailyMedID = Tamoxifen [17] => | pregnancy_AU = B3 [18] => | pregnancy_AU_comment = {{cite web | title=Tamoxifen Use During Pregnancy | website=Drugs.com | date=25 July 2019 | url=https://www.drugs.com/pregnancy/tamoxifen.html | access-date=27 January 2020}} [19] => | pregnancy_category= [20] => | routes_of_administration = [[Oral administration|By mouth]] [21] => | class = [[Selective estrogen receptor modulator]] [22] => | ATC_prefix = L02 [23] => | ATC_suffix = BA01 [24] => [25] => [26] => | legal_AU = S4 [27] => | legal_AU_comment = [28] => | legal_BR = [29] => | legal_BR_comment = [30] => | legal_CA = Rx-only [31] => | legal_CA_comment = [32] => | legal_DE = [33] => | legal_DE_comment = [34] => | legal_NZ = [35] => | legal_NZ_comment = [36] => | legal_UK = POM [37] => | legal_UK_comment = [38] => | legal_US = Rx-only [39] => | legal_US_comment = {{cite web | title=Tamoxifen citrate tablet, film coated | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c82205a3-ae0c-4ce5-b04b-9581cd8c70d4 | access-date=12 September 2021}}{{cite web | title=Soltamox- tamoxifen citrate liquid | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1e6ff055-590c-41e6-9530-1fdf04cdbd02 | access-date=12 September 2021}} [40] => | legal_EU = [41] => | legal_EU_comment = [42] => | legal_UN = [43] => | legal_UN_comment = [44] => | legal_status = [45] => [46] => [47] => | bioavailability = ~100% [48] => | protein_bound = >99% ([[human serum albumin|albumin]]) [49] => | metabolism = [[Liver]] ([[CYP3A4]], [[CYP2C9]], [[CYP2D6]]){{cite web | title=Nolvadex (Tamoxifen Citrate) tablets | website=DailyMed | date=3 November 2016 | url=https://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=234988 | access-date=12 September 2021}} [50] => | metabolites = • [[N-Desmethyltamoxifen|''N''-Desmethyltamoxifen]]
• [[Endoxifen]] (4-hydroxy-''N''-desmethyltamoxifen)
• [[Afimoxifene]] (4-hydroxytamoxifen)
• [[N,N-Didesmethyltamoxifen|''N'',''N''-Didesmethyltamoxifen]]
• [[Norendoxifen]] (4-hydroxy-''N'',''N''-didesmethyltamoxifen)
• Others, [[conjugation (biochemistry)|conjugates]] [51] => | onset = [52] => | elimination_half-life = 5–7 days [53] => | duration_of_action = [54] => | excretion = [[Feces]]: 65%
[[Urine]]: 9% [55] => [56] => [57] => | index2_label = citrate [58] => | CAS_number_Ref = {{cascite|correct|??}} [59] => | CAS_number = 10540-29-1 [60] => | CAS_number2 = 54965-24-1 [61] => | PubChem = 2733526 [62] => | PubChem2 = 2733525 [63] => | IUPHAR_ligand = 1016 [64] => | DrugBank_Ref = {{drugbankcite|correct|drugbank}} [65] => | DrugBank = DB00675 [66] => | DrugBank2 = DBSALT000168 [67] => | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} [68] => | ChemSpiderID = 2015313 [69] => | ChemSpiderID2 = 2015312 [70] => | UNII_Ref = {{fdacite|correct|FDA}} [71] => | UNII = 094ZI81Y45 [72] => | UNII2 = 7FRV7310N6 [73] => | KEGG_Ref = {{keggcite|correct|kegg}} [74] => | KEGG = D08559 [75] => | KEGG2 = D00966 [76] => | ChEBI_Ref = {{ebicite|correct|EBI}} [77] => | ChEBI = 41774 [78] => | ChEBI2 = 9397 [79] => | ChEMBL_Ref = {{ebicite|correct|EBI}} [80] => | ChEMBL = 83 [81] => | ChEMBL2 = 786 [82] => | NIAID_ChemDB = [83] => | PDB_ligand = CTX [84] => | synonyms = TMX; ICI-46474 [85] => [86] => [87] => | IUPAC_name = (''Z'')-2-[4-(1,2-Diphenylbut-1-enyl)phenoxy]-''N'',''N''-dimethylethanamine [88] => | C=26 | H=29 | N=1 | O=1 [89] => | SMILES = CN(C)CCOc1ccc(cc1)/C(c2ccccc2)=C(/CC)c3ccccc3 [90] => | StdInChI_Ref = {{stdinchicite|correct|chemspider}} [91] => | 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- [92] => | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} [93] => | StdInChIKey = NKANXQFJJICGDU-QPLCGJKRSA-N [94] => }} [95] => [96] => [97] => '''Tamoxifen''', sold under the brand name '''Nolvadex''' among others, is a [[selective estrogen receptor modulator]] used to prevent [[breast cancer]] in women and men.{{cite web|title=Tamoxifen Citrate|url=http://www.cancer.gov/about-cancer/treatment/drugs/tamoxifencitrate|website=NCI|access-date=28 November 2015|date=26 August 2015|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}} It is also being studied for other types of [[cancer]]. It has been used for [[Albright syndrome]]. Tamoxifen is typically taken daily [[oral administration|by mouth]] for five years for breast cancer.{{cite web|title=Tamoxifen Citrate|url=https://www.drugs.com/monograph/tamoxifen-citrate.html|work=The American Society of Health-System Pharmacists|access-date=27 November 2015|url-status=live|archive-url=https://web.archive.org/web/20140104090258/http://www.drugs.com/monograph/tamoxifen-citrate.html|archive-date=4 January 2014}} [98] => [99] => [100] => Serious side effects include a small increased risk of [[uterine cancer]], [[stroke]], vision problems, and [[pulmonary embolism]]. Common side effects include [[irregular menstruation|irregular periods]], weight loss, and [[hot flashes]]. It may cause harm to the baby if taken during [[pregnancy]] or [[breastfeeding]]. It is a [[selective estrogen-receptor modulator]] (SERM) and works by decreasing the growth of breast cancer cells.{{cite web|title=Selective estrogen receptor modulators|url=https://www.drugs.com/drug-class/selective-estrogen-receptor-modulators.html|access-date=28 November 2015|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}} It is a member of the [[triphenylethylene]] group of [[chemical compound|compound]]s.{{cite book |veditors=Cano A, Calaf i Alsina J, Duenas-Diez JL |title=Selective Estrogen Receptor Modulators a New Brand of Multitarget Drugs|date=2006|publisher=Springer-Verlag Berlin Heidelberg|location=Berlin, Heidelberg|isbn=9783540347422|page=52|url=https://books.google.com/books?id=heJDAAAAQBAJ&pg=PA52}} [101] => [102] => [103] => Tamoxifen was initially made in 1962, by chemist Dora Richardson.{{cite journal | vauthors = Jordan VC | 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 | date = January 2006 | pmid = 16402113 | pmc = 1760730 | doi = 10.1038/sj.bjp.0706399 }} It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }} Tamoxifen is available as a [[generic medication]]. In 2020, it was the 317th most commonly prescribed medication in the United States, with more than 900{{nbsp}}thousand prescriptions.{{cite web | title = The Top 300 of 2020 | url = https://clincalc.com/DrugStats/Top300Drugs.aspx | website = ClinCalc | access-date = 7 October 2022}}{{cite web | title = Tamoxifen Citrate - Drug Usage Statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/TamoxifenCitrate | access-date = 7 October 2022 | archive-date = 22 September 2020 | archive-url = https://web.archive.org/web/20200922010115/https://clincalc.com/DrugStats/Drugs/TamoxifenCitrate | url-status = dead }} [104] => {{TOC limit}} [105] => [106] => ==Medical uses== [107] => [108] => ===Dysmenorrhea=== [109] => Tamoxifen has been used effectively to improve blood flow, reduce uterine contractility and pain in dysmenorrhea patients.{{cite journal |vauthors=Thomas B, Magos A | title = Modern management of dysmenorrhoea | journal = Trends in Urology, Gynaecology & Sexual Health | date = 2009 | volume = 14 | issue = 5 | pages = 25–29 | doi = 10.1002/tre.120 | doi-access = free }} [110] => [111] => ===Breast cancer=== [112] => 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.{{cite journal | vauthors = Jordan VC | 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 | date = October 1993 | pmid = 8242225 | pmc = 2175926 | doi = 10.1111/j.1476-5381.1993.tb13840.x }} 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.{{cite journal | vauthors = Romero SA, Young K, Hickey M, Su HI | title = Levonorgestrel intrauterine system for endometrial protection in women with breast cancer on adjuvant tamoxifen | journal = The Cochrane Database of Systematic Reviews | volume = 12 | pages = CD007245 | date = December 2020 | issue = 2 | pmid = 33348436 | doi = 10.1002/14651858.CD007245.pub4 | pmc = 8092675 }} Additionally, it is the most common hormone treatment for male breast cancer.{{cite web| url =http://www.cancerhelp.org.uk/help/default.asp?page=5075| title =Breast cancer in men| date =28 September 2007| work =CancerHelp UK| publisher =Cancer Research UK| 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| url-status =dead}} 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.{{cite web | url = https://www.fda.gov/cder/news/tamoxifen/| title = Tamoxifen Information: reducing the incidence of breast cancer in women at high risk | access-date = 3 July 2007| author = Center for Drug Evaluation and Research | date = 7 July 2005 | publisher = U.S. Food and Drug Administration |archive-url = https://web.archive.org/web/20070619012859/https://www.fda.gov/cder/news/tamoxifen/ |archive-date = 19 June 2007}} It has been further approved for the reduction of contralateral (in the opposite breast) cancer. The use of tamoxifen is recommended for 10 years.{{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 | display-authors = 6 | 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 | date = July 2014 | pmid = 24868023 | pmc = 4876310 | doi = 10.1200/JCO.2013.54.2258 }} [113] => [114] => 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.{{cite web| url = http://www.cancer.gov/star| title = Study of Tamoxifen and Raloxifene (STAR) Trial| access-date = 3 July 2007| author = National Cancer Institute| date = 26 April 2006| publisher = U.S. National Institutes of Health| url-status = dead| archive-url = https://web.archive.org/web/20070704091218/http://www.cancer.gov/star| archive-date = 4 July 2007}}{{cite web | url = http://www.nsabp.pitt.edu/STAR/Index.html| title = STAR Study of Tamoxifen and Raloxifen | access-date = 3 July 2007| author = University of Pittsburgh |archive-url = https://web.archive.org/web/20070611194336/http://www.nsabp.pitt.edu/STAR/Index.html |archive-date = 11 June 2007}}{{cite web | url = http://www.dslrf.org/breastcancer/content.asp?L2=2&L3=6&SID=130&CID=391&PID=14&CATID=0 | title = Study Finds New Use for Raloxifene: Reducing Breast Cancer in High-Risk Postmenopausal Women | access-date = 19 March 2009 | vauthors = Love S | author-link1 = Susan Love | date = 22 April 2006 | 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 }} [115] => [116] => ===Infertility=== [117] => 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.{{cite journal | vauthors = Steiner AZ, Terplan M, Paulson RJ | title = Comparison of tamoxifen and clomiphene citrate for ovulation induction: a meta-analysis | journal = Human Reproduction | volume = 20 | issue = 6 | pages = 1511–1515 | date = June 2005 | pmid = 15845599 | doi = 10.1093/humrep/deh840 | doi-access = free }} [118] => [119] => 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.{{cite journal | vauthors = Chua ME, Escusa KG, Luna S, Tapia LC, Dofitas B, Morales M | 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 | date = September 2013 | pmid = 23970453 | doi = 10.1111/j.2047-2927.2013.00107.x | s2cid = 38345293 | doi-access = free }} [120] => [121] => ===Gynecomastia=== [122] => Tamoxifen is used to prevent and treat [[gynecomastia]].{{cite journal | vauthors = Lapid O, van Wingerden JJ, Perlemuter L | 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 | year = 2013 | pmid = 23729603 | doi = 10.1515/jpem-2013-0052 | s2cid = 2101602 }}{{cite journal | vauthors = Viani GA, Bernardes da Silva LG, Stefano EJ | 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 | date = July 2012 | pmid = 22704706 | doi = 10.1016/j.ijrobp.2012.01.036 }} It is taken as a preventative measure in small doses, or used at the onset of any symptoms such as nipple soreness or sensitivity. Other medications are taken for similar purposes such as [[clomifene]] and the anti-aromatase drugs which are used in order to try to avoid the hormone-related adverse effects. [123] => [124] => {{Tamoxifen dosage and incidence of breast symptoms with bicalutamide in men}} [125] => [126] => ===Early puberty=== [127] => Tamoxifen is useful in the treatment of [[peripheral precocious puberty]], for instance due to [[McCune–Albright syndrome]], in both girls and boys.{{cite journal | vauthors = Neyman A, Eugster EA | 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 | date = December 2017 | pmid = 29292624 | pmc = 5808444 | doi = 10.17458/per.vol15.2017.nau.treatmentgirlsboys }}{{cite journal | vauthors = Haddad NG, Eugster EA | 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 | date = June 2019 | pmid = 31027974 | doi = 10.1016/j.beem.2019.04.007 | hdl-access = free | s2cid = 135410503 | hdl = 1805/19111 }}{{cite book | vauthors = Zacharin M | title = Pediatric Pharmacotherapy | chapter = Disorders of Puberty: Pharmacotherapeutic Strategies for Management | series = Handbook of Experimental Pharmacology | volume = 261 | pages = 507–538 | date = May 2019 | pmid = 31144045 | doi = 10.1007/164_2019_208 | isbn = 978-3-030-50493-9 | s2cid = 169040406 }} 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. [128] => [129] => ===Available forms=== [130] => [[File:Nolvadex.jpg|thumb|right|250px|Nolvadex (tamoxifen) 20 mg tablets.]] [131] => [132] => Tamoxifen is available as a tablet or oral solution.Product Information: tamoxifen citrate oral tablets, tamoxifen citrate oral tablets. Watson Laboratories (per manufacturer), Corona, CA, 2011.Product Information: SOLTAMOX(R) oral solution, tamoxifen citrate oral solution. Midatech Pharma US Inc (per FDA), Raleigh, NC, 2018. [133] => [134] => ==Contraindications== [135] => 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]]). [136] => [137] => ==Side effects== [138] => 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.{{cite web|url=http://www.oncogenetics.org/web/Medications-Effective-in-Reducing-Risk-of-Breast-Cancer-But-Increase-Risk-of-Adverse-Effects |title=Medications Effective in Reducing Risk of Breast Cancer But Increase Risk of Adverse Effects |author=OncoGenetics.Org |publisher=OncoGenetics.Org |access-date=14 September 2009 |date=September 2009 |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 }} [139] => [140] => ===Endometrial cancer=== [141] => Tamoxifen is a [[selective estrogen receptor modulator]] (SERM).{{cite journal | vauthors = Gallo MA, Kaufman D | 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 | date = February 1997 | pmid = 9045319 }} 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.{{cite journal | vauthors = Grilli S | title = Tamoxifen (TAM): the dispute goes on | journal = Annali dell'Istituto Superiore di Sanità | volume = 42 | issue = 2 | pages = 170–173 | year = 2006 | pmid = 17033137 | url = http://www.iss.it/publ/anna/2006/2/422170.pdf | url-status = dead | access-date = 3 July 2007 | archive-url = https://web.archive.org/web/20070810113431/http://www.iss.it/publ/anna/2006/2/422170.pdf | archive-date = 10 August 2007 }} With time, risk of endometrial cancer may be doubled to quadrupled, which is a reason tamoxifen is typically only used for five years.{{cite web |url = http://healthlifeandstuff.com/2009/12/tamoxifen-for-breast-cancer-side-effects/ |title = Tamoxifen for Breast Cancer & Side Effects |publisher = Health and Life |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 |date = 11 December 2009 }} [142] => [143] => 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.{{cite web| url =http://www.cancer.org/docroot/PED/content/PED_1_3x_Known_and_Probable_Carcinogens.asp?sitearea=PED| title =Known and Probable Carcinogens| access-date =21 March 2008| date =3 February 2006| publisher =American Cancer Society| 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| url-status =live}} [144] => [145] => ===Cardiovascular and metabolic=== [146] => 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.{{cite journal | vauthors = Esteva FJ, Hortobagyi GN | 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 | date = June 2006 | pmid = 16230014 | doi = 10.1016/j.breast.2005.08.033 }} 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.{{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 | display-authors = 6 | title = Effect of tamoxifen on venous thromboembolic events in a breast cancer prevention trial | journal = Circulation | volume = 111 | issue = 5 | pages = 650–656 | date = February 2005 | pmid = 15699284 | doi = 10.1161/01.CIR.0000154545.84124.AC | doi-access = free }} Use of tamoxifen has been shown to slightly increase risk of [[deep vein thrombosis]], [[pulmonary embolism]], and [[stroke]].{{cite journal | vauthors = Harvey HA, Kimura M, Hajba A | title = Toremifene: an evaluation of its safety profile | journal = Breast | volume = 15 | issue = 2 | pages = 142–157 | date = April 2006 | pmid = 16289904 | doi = 10.1016/j.breast.2005.09.007 }} [147] => [148] => ===Liver toxicity=== [149] => Tamoxifen has been associated with a number of cases of [[hepatotoxicity]].{{cite book| vauthors = Cameron R, Feuer G, de la Iglesia F |title=Drug-Induced Hepatotoxicity|url=https://books.google.com/books?id=xZf-CAAAQBAJ&pg=PA565|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-61013-4|pages=565–}} Several different varieties of hepatotoxicity have been reported. 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 mg/day.{{cite journal | vauthors = Osman KA, Osman MM, Ahmed MH | 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 | date = January 2007 | pmid = 17181445 | doi = 10.1517/14740338.6.1.1 | s2cid = 33505288 }} [150] => [151] => ==Overdose== [152] => Acute [[overdose]] of tamoxifen has not been reported in humans. In [[dose-ranging study|dose-ranging studies]], tamoxifen was administered at very high doses in women (e.g., 300 mg/m2) and was found to produce acute [[neurotoxicity]] including [[tremor]], [[hyperreflexia]], [[gait abnormality|unsteady gait]], and [[dizziness]]. These symptoms occurred within three to five days of therapy and disappeared within two to five days of discontinuation of therapy. No indications of permanent neurotoxicity were observed. [[QT prolongation]] was also observed with very high doses of tamoxifen. There is no specific [[antidote]] for overdose of tamoxifen. Instead, treatment should be based on [[symptom]]s. [153] => [154] => == Interactions == [155] => [156] => 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.{{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 | display-authors = 6 | 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 | date = December 2005 | pmid = 16361630 | doi = 10.1200/JCO.2005.03.3266 | doi-access = free }}{{cite journal | vauthors = Beverage JN, Sissung TM, Sion AM, Danesi R, Figg WD | title = CYP2D6 polymorphisms and the impact on tamoxifen therapy | journal = Journal of Pharmaceutical Sciences | volume = 96 | issue = 9 | pages = 2224–2231 | date = September 2007 | pmid = 17518364 | doi = 10.1002/jps.20892 }} On 18 October 2006, the Subcommittee for Clinical Pharmacology recommended relabeling tamoxifen to include information about this gene in the package insert.[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 }} Certain CYP2D6 variations in breast cancer patients lead to a worse clinical outcome for tamoxifen treatment.{{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 | display-authors = 6 | 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 | date = October 2009 | pmid = 19809024 | pmc = 3909953 | doi = 10.1001/jama.2009.1420 }} [[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.[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 }} Other molecular biomarkers may also be used to select appropriate patients likely to benefit from tamoxifen.{{cite journal | vauthors = Criscitiello C, Fumagalli D, Saini KS, Loi S | 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 | date = December 2010 | pmid = 21552410 | pmc = 3084302 | doi = 10.2147/OTT.S10155 | doi-access = free }} [157] => [158] => 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.{{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 | display-authors = 6 | 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 | date = January 2005 | pmid = 15632378 | doi = 10.1093/jnci/dji005 | doi-access = free }} 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.{{cite news | author = Staff Reports | title = ASCO Updates: Antidepressants Reduce the Effectiveness of Tamoxifen. | date =Summer 2009 | publisher = CURE (Cancer Updates, Research and Education) | 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 }} 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.{{cite journal | vauthors = Kelly CM, Juurlink DN, Gomes T, Duong-Hua M, Pritchard KI, Austin PC, Paszat LF | title = Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study | journal = BMJ | volume = 340 | pages = c693 | date = February 2010 | pmid = 20142325 | pmc = 2817754 | doi = 10.1136/bmj.c693 }} [159] => [160] => Tamoxifen interacts with certain other [[antiestrogen]]s. The [[aromatase inhibitor]] [[aminoglutethimide]] induces the metabolism of tamoxifen. Conversely, the aromatase inhibitor [[letrozole]] does not affect the metabolism of tamoxifen. However, tamoxifen induces the metabolism of letrozole and significantly reduces its concentrations. [161] => [162] => ==Pharmacology== [163] => [164] => ===Pharmacodynamics=== [165] => [166] => ====Selective estrogen receptor modulator activity==== [167] => [[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).{{PDB|3ERT}}; {{cite journal | vauthors = Shiau AK, Barstad D, Loria PM, Cheng L, Kushner PJ, Agard DA, Greene GL | 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 | date = December 1998 | pmid = 9875847 | doi = 10.1016/S0092-8674(00)81717-1 | s2cid = 10265320 | doi-access = free }}]] [168] => [169] => 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.{{cite journal | vauthors = Wang DY, Fulthorpe R, Liss SN, Edwards EA | 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 | date = February 2004 | pmid = 14605097 | doi = 10.1210/me.2003-0202 | doi-access = free }} 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]].{{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 | display-authors = 6 | 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 | date = September 2007 | pmid = 17803905 | doi = 10.1016/j.cell.2007.07.025 | s2cid = 17177462 | doi-access = free }}{{cite journal | vauthors = Krum SA, Miranda-Carboni GA, Hauschka PV, Carroll JS, Lane TF, Freedman LP, Brown M | 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 | date = February 2008 | pmid = 18219273 | pmc = 2241656 | doi = 10.1038/sj.emboj.7601984 }} 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.{{cite journal | vauthors = Mincey BA, Moraghan TJ, Perez EA | title = Prevention and treatment of osteoporosis in women with breast cancer | journal = Mayo Clinic Proceedings | volume = 75 | issue = 8 | pages = 821–829 | date = August 2000 | pmid = 10943237 | doi = 10.4065/75.8.821 | doi-access = free }} [170] => [171] => {{Tissue-specific estrogenic and antiestrogenic activity of SERMs}} [172] => [173] => Tamoxifen is a long-acting SERM, with a [[nuclear retention]] of the ER–tamoxifen (or metabolite) complex of greater than 48 hours.{{cite book| vauthors = Runnebaum B, Rabe T |title=Gynäkologische Endokrinologie und Fortpflanzungsmedizin: Band 1: Gynäkologische Endokrinologie|url=https://books.google.com/books?id=mBF9BwAAQBAJ&pg=PA88|date=17 April 2013|publisher=Springer-Verlag|isbn=978-3-662-07635-4|pages=88–}}{{cite journal | vauthors = Hammond CB, Maxson WS | title = Current status of estrogen therapy for the menopause | journal = Fertility and Sterility | volume = 37 | issue = 1 | pages = 5–25 | date = January 1982 | pmid = 6277697 | doi = 10.1016/S0015-0282(16)45970-4 | doi-access = free }} 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). These metabolites have approximately 30 to 100 times greater affinity for the ERs than tamoxifen itself.{{cite journal | vauthors = Ahmad A, Shahabuddin S, Sheikh S, Kale P, Krishnappa M, Rane RC, Ahmad I | 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 | date = December 2010 | pmid = 20981001 | doi = 10.1038/clpt.2010.196 | s2cid = 24590365 }} 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.{{cite journal | vauthors = Kuhl H | title = Pharmacology of estrogens and progestogens: influence of different routes of administration | journal = Climacteric | volume = 8 | issue = Suppl 1 | pages = 3–63 | date = August 2005 | pmid = 16112947 | doi = 10.1080/13697130500148875 | s2cid = 24616324 }} Hence, afimoxifene showed 25-fold higher affinity for the ERα and 56-fold higher affinity for the ERβ than tamoxifen.{{cite journal | vauthors = Potts RO, Lobo RA | title = Transdermal drug delivery: clinical considerations for the obstetrician-gynecologist | journal = Obstetrics and Gynecology | volume = 105 | issue = 5 Pt 1 | pages = 953–961 | date = May 2005 | pmid = 15863530 | doi = 10.1097/01.AOG.0000161958.70059.db | s2cid = 23411589 }} The antiestrogenic potencies of endoxifen and afimoxifene are very similar. However, endoxifen occurs in much higher concentrations than afimoxifene and is now thought to be the major active form of tamoxifen in the body.{{cite journal | vauthors = Binkhorst L, Mathijssen RH, Jager A, van Gelder T | title = Individualization of tamoxifen therapy: much more than just CYP2D6 genotyping | journal = Cancer Treatment Reviews | volume = 41 | issue = 3 | pages = 289–299 | date = March 2015 | pmid = 25618289 | doi = 10.1016/j.ctrv.2015.01.002 }} [174] => [175] => 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 G0 and G1 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]].{{cite journal | vauthors = Shang Y, Hu X, DiRenzo J, Lazar MA, Brown M | title = Cofactor dynamics and sufficiency in estrogen receptor-regulated transcription | journal = Cell | volume = 103 | issue = 6 | pages = 843–852 | date = December 2000 | pmid = 11136970 | doi = 10.1016/S0092-8674(00)00188-4 | s2cid = 6659079 | doi-access = free }} Tamoxifen function can be regulated by a number of different variables including growth factors.{{cite journal | vauthors = Massarweh S, Osborne CK, Creighton CJ, Qin L, Tsimelzon A, Huang S, Weiss H, Rimawi M, Schiff R | display-authors = 6 | 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 | date = February 2008 | pmid = 18245484 | doi = 10.1158/0008-5472.CAN-07-2707 | doi-access = free }} Tamoxifen needs to block growth factor proteins such as [[ERBB2|ErbB2/HER2]]{{cite journal | vauthors = Hurtado A, Holmes KA, Geistlinger TR, Hutcheson IR, Nicholson RI, Brown M, Jiang J, Howat WJ, Ali S, Carroll JS | display-authors = 6 | title = Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen | journal = Nature | volume = 456 | issue = 7222 | pages = 663–666 | date = December 2008 | pmid = 19005469 | pmc = 2920208 | doi = 10.1038/nature07483 | bibcode = 2008Natur.456..663H }} because high levels of ErbB2 have been shown to occur in tamoxifen resistant cancers.{{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 | display-authors = 6 | 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 | date = March 2003 | pmid = 12618500 | doi = 10.1093/jnci/95.5.353 | doi-access = free }} Tamoxifen seems to require a protein [[PAX2]] for its full anticancer effect.{{cite web| url =http://www.modernmedicine.com/modernmedicine/Modern+Medicine+Now/New-Mechanism-Predicts-Tamoxifen-Response/ArticleNewsFeed/Article/detail/565990| title =New Mechanism Predicts Tamoxifen Response: PAX2 gene implicated in tamoxifen-induced inhibition of ERBB2/HER2-mediated tumor growth| date =13 November 2008| publisher =www.modernmedicine.com| 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| url-status =live}} 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.{{cite web| url =http://cordis.europa.eu/fetch?CALLER=EN_NEWS&ACTION=D&SESSION=&RCN=30093| title =Study sheds new light on tamoxifen resistance| work =News| publisher =CORDIS News| 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| url-status =live}} [176] => [177] => 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. However, it has [[progonadotropic]] effects in [[premenopausal]] women and increases estrogen levels by 6-fold in them.{{cite journal | vauthors = Li J, Ma Z, Jiang RW, Wu B | 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 | date = September 2013 | pmid = 23687971 | doi = 10.1517/17425255.2013.802771 | s2cid = 26846314 }} 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. 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 mg/day in women with breast cancer.{{cite journal | vauthors = Fabian CJ, Kimler BF | title = Selective estrogen-receptor modulators for primary prevention of breast cancer | journal = Journal of Clinical Oncology | volume = 23 | issue = 8 | pages = 1644–1655 | date = March 2005 | pmid = 15755972 | doi = 10.1200/JCO.2005.11.005 | doi-access = free }} Tamoxifen has been found to decrease [[insulin-like growth factor 1]] (IGF-1) levels by 17 to 38% in women and men.{{cite journal | vauthors = Duarte FH, Jallad RS, Bronstein MD | title = Estrogens and selective estrogen receptor modulators in acromegaly | journal = Endocrine | volume = 54 | issue = 2 | pages = 306–314 | date = November 2016 | pmid = 27704479 | doi = 10.1007/s12020-016-1118-z | s2cid = 10136018 }} Suppression of IGF-1 production in the liver is a well-known action of estrogens and SERMs. A 10 mg/day dosage of tamoxifen is nearly as effective as a 20 mg/day dosage in suppressing IGF-1 levels.{{cite journal | vauthors = Morello KC, Wurz GT, DeGregorio MW | title = Pharmacokinetics of selective estrogen receptor modulators | journal = Clinical Pharmacokinetics | volume = 42 | issue = 4 | pages = 361–372 | year = 2003 | pmid = 12648026 | doi = 10.2165/00003088-200342040-00004 | s2cid = 13003168 }} [178] => [179] => ====Other activities==== [180] => Afimoxifene is an [[agonist]] of the [[G protein-coupled estrogen receptor]] (GPER) with relatively low [[affinity (pharmacology)|affinity]].{{cite journal | vauthors = Prossnitz ER, Arterburn JB | 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 | date = July 2015 | pmid = 26023144 | pmc = 4485017 | doi = 10.1124/pr.114.009712 }} Its affinity for the receptor is in the range of 100 to 1,000 nM, relative to 3 to 6 nM for estradiol. [181] => [182] => 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).{{cite journal | vauthors = Ariazi EA, Jordan VC | 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 | date = 2006 | pmid = 16515477 | doi = 10.2174/1568026610606030203 }} [183] => [184] => [[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|IC50]] = 90 nM), and may also be involved in the antiestrogenic activity of tamoxifen.{{cite journal | vauthors = Liu J, Flockhart PJ, Lu D, Lv W, Lu WJ, Han X, Cushman M, Flockhart DA | display-authors = 6 | 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 | date = September 2013 | pmid = 23824607 | pmc = 3876808 | doi = 10.1124/dmd.113.052506 }} [185] => [186] => 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.{{cite journal | vauthors = Zarate CA, Manji HK | 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 | year = 2009 | pmid = 19552485 | pmc = 2802274 | doi = 10.2165/00023210-200923070-00003 }} This action is thought to underlie the efficacy of tamoxifen in the treatment of [[bipolar disorder]]. [187] => [188] => Tamoxifen is an inhibitor of [[P-glycoprotein]]. [189] => [190] => ===Pharmacokinetics=== [191] => [192] => ====Absorption==== [193] => Tamoxifen is rapidly and extensively [[absorption (pharmacokinetics)|absorbed]] from the [[intestine]]s with [[oral administration]].{{cite book| vauthors = Brenner GM, Stevens C |title=Brenner and Stevens' Pharmacology E-Book|url=https://books.google.com/books?id=v3g4DwAAQBAJ&pg=PA394|date=28 September 2017|publisher=Elsevier Health Sciences|isbn=978-0-323-39172-6|pages=394–}} The [[oral administration|oral]] [[bioavailability]] of tamoxifen is approximately 100%, which is suggestive of minimal [[first-pass metabolism]] in the intestines and [[liver]]. Following intake, [[peak levels]] of tamoxifen occur after three to seven hours. [[Steady state levels]] of tamoxifen are reached typically after 3 to 4 weeks but possibly up to 16 weeks of daily administration. Steady state levels of afimoxifene are achieved after 8 weeks of daily tamoxifen administration.{{cite book | vauthors = Nagar S | title = Chemo Fog | chapter = Pharmacokinetics of Anti-Cancer Drugs Used in Breast Cancer Chemotherapy | series = Advances in Experimental Medicine and Biology | volume = 678 | pages = 124–132 | year = 2010 | pmid = 20738014 | doi = 10.1007/978-1-4419-6306-2_16 | isbn = 978-1-4419-6305-5 | s2cid = 12537667 }}{{cite book| vauthors = Chabner BA, Longo DL |title=Cancer Chemotherapy and Biotherapy: Principles and Practice|url=https://books.google.com/books?id=0U4aj4GZWCIC&pg=PA655|date=7 December 2011|publisher=Lippincott Williams & Wilkins|isbn=978-1-4511-4820-6|pages=655–}} Peak levels of tamoxifen after a single 40 mg oral dose were 65 ng/mL and steady state levels at 20 mg/day were 310 ng/mL. Levels of tamoxifen show clear [[dose dependency]] across a dosage range of 1 to 20 mg/day.{{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 | display-authors = 6 | 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 | date = April 2004 | pmid = 15073109 | doi = 10.1158/1078-0432.ccr-03-0538 | doi-access = free }} Endoxifen levels are approximately 5 to 10 times higher than afimoxifene levels, with large [[interindividual variability]]. Endoxifen levels have been reported as 10.8 to 15.9 ng/mL at steady state in [[CYP2D6]] normal metabolizers during therapy with 20 mg/day tamoxifen. 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.{{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 | display-authors = 6 | 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 | date = May 2011 | pmid = 21451508 | doi = 10.1038/clpt.2011.27 | s2cid = 20082053 }}{{cite journal | vauthors = Jordan VC | 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 | date = 1982 | pmid = 6184101 | doi = 10.1007/BF01806449 | s2cid = 25119313 }} [194] => [195] => ====Distribution==== [196] => The [[volume of distribution]] of tamoxifen is 50 to 60 L/kg and its [[clearance (pharmacology)|clearance]] has been estimated as 1.2 to 5.1 L/hour.{{cite book| vauthors = DeVita VT, Lawrence TS, Rosenberg SA | author-link2 = Theodore S. Lawrence |title=Prostate and Other Genitourinary Cancers: From Cancer: Principles & Practice of Oncology, 10th edition|url=https://books.google.com/books?id=Bf3DCwAAQBAJ&pg=PT990|date=18 March 2016|publisher=Wolters Kluwer Health|isbn=978-1-4963-5421-1|pages=990–}} High concentrations of tamoxifen have been found in [[breast]], [[uterus]], liver, [[kidney]], [[lung]], [[pancreas]], and [[ovary]] tissue in animals and humans. Levels of tamoxifen in the uterus have been found to be 2- to 3-fold higher than in the circulation and in the breasts 10-fold higher than in the circulation. The [[plasma protein binding]] of tamoxifen and afimoxifene is greater than 99%. A majority of tamoxifen is bound to [[human serum albumin|albumin]]. Albumin alone binds 98.8% of tamoxifen while other [[plasma protein]]s are not greatly involved.{{cite journal | vauthors = Lien EA, Solheim E, Lea OA, Lundgren S, Kvinnsland S, Ueland PM | title = Distribution of 4-hydroxy-N-desmethyltamoxifen and other tamoxifen metabolites in human biological fluids during tamoxifen treatment | journal = Cancer Research | volume = 49 | issue = 8 | pages = 2175–2183 | date = April 1989 | pmid = 2702659 | url = https://cancerres.aacrjournals.org/content/49/8/2175.short }} [197] => [198] => ====Metabolism==== [199] => {| class="wikitable floatright" [200] => |+Tamoxifen and its metabolites in humans{{cite journal | vauthors = Brauch H, Mürdter TE, Eichelbaum M, Schwab M | title = Pharmacogenomics of tamoxifen therapy | journal = Clinical Chemistry | volume = 55 | issue = 10 | pages = 1770–1782 | date = October 2009 | pmid = 19574470 | doi = 10.1373/clinchem.2008.121756 | doi-access = free }} [201] => !Compound [202] => !Mean plasma
concentrations [203] => !Effect on ER / affinity for ERa [204] => |- [205] => |Tamoxifen [206] => |190–420 nmol/L [207] => |Weak antagonist / 2% [208] => |- [209] => |[[N-Desmethyltamoxifen|''N''-Desmethyltamoxifen]] [210] => |280–800 nmol/L [211] => |Weak antagonist / 1% [212] => |- [213] => |[[N,N-Desmethyltamoxifen|''N'',''N''-Desmethyltamoxifen]] [214] => |90–120 nmol/L [215] => |Weak antagonist [216] => |- [217] => |[[Endoxifen]] [218] => |14–130 nmol/L [219] => |Strong antagonist / equal to afimoxifene [220] => |- [221] => |[[Afimoxifene]] [222] => |3–17 nmol/Lb [223] => |Strong antagonist / 188% [224] => |- [225] => |α-Hydroxytamoxifen [226] => |1 nmol/L [227] => |None [228] => |- [229] => |3,4-Dihydroxytamoxifen [230] => |? [231] => |Weak antagonist / high affinity [232] => |- [233] => |Tamoxifen ''N''-oxide [234] => |15–24 nmol/L [235] => |Weak antagonistc [236] => |- [237] => | colspan="3" style="width: 1px; background-color:#eaecf0; text-align: center;" | '''Footnotes:''' a = Estradiol is 100%. b = One study reported a much higher concentration (67 nmol/L). c = Might be due to reduction to tamoxifen. [238] => |} [239] => [240] => 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).{{cite journal | vauthors = Sanchez-Spitman AB, Swen JJ, Dezentje VO, Moes DJ, Gelderblom H, Guchelaar HJ | title = Clinical pharmacokinetics and pharmacogenetics of tamoxifen and endoxifen | journal = Expert Review of Clinical Pharmacology | volume = 12 | issue = 6 | pages = 523–536 | date = June 2019 | pmid = 31008668 | doi = 10.1080/17512433.2019.1610390 | doi-access = free }} 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.{{cite journal | vauthors = Klein DJ, Thorn CF, Desta Z, Flockhart DA, Altman RB, Klein TE | title = PharmGKB summary: tamoxifen pathway, pharmacokinetics | journal = Pharmacogenetics and Genomics | volume = 23 | issue = 11 | pages = 643–647 | date = November 2013 | pmid = 23962908 | pmc = 4084801 | doi = 10.1097/FPC.0b013e3283656bc1 }} Conversely, 4-hydroxylation of tamoxifen into afimoxifene is responsible for only about 7% of tamoxifen metabolism. Following its formation, ''N''-desmethyltamoxifen is [[oxidation|oxidized]] into several other metabolites, the most notable of which is endoxifen. 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]]. Tamoxifen and its metabolites undergo [[conjugation (biochemistry)|conjugation]], including [[glucuronidation]] and [[sulfation]]. Tamoxifen may inhibit its own metabolism. [241] => [242] => ====Elimination==== [243] => Tamoxifen has a long [[elimination half-life]] of typically 5 to 7 days, with a range of 4 to 11 days. Similarly, the half-life of afimoxifene is 14 days. Conversely, the half-life of [[endoxifen]] is 50 to 70 hours (2–3 days). The long half-lives of tamoxifen and afimoxifene are attributed to their high plasma protein binding as well as to [[enterohepatic recirculation]]. Upon discontinuation of treatment, levels of tamoxifen and its metabolites persist in the circulation for at least 6 weeks. Tamoxifen is [[excretion|excreted]] in [[bile]] and is [[elimination (pharmacology)|eliminated]] in [[feces]], while small amounts are eliminated in [[urine]]. [244] => [245] => ==Chemistry== [246] => 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]].{{cite book| vauthors = Jordan VC |title=Estrogen/antiestrogen Action and Breast Cancer Therapy|url=https://books.google.com/books?id=7WmLZfGXST0C&pg=PA28|year=1986|publisher=Univ of Wisconsin Press|isbn=978-0-299-10480-1|pages=28,154}}{{cite book| vauthors = Pratt WB |title=The Anticancer Drugs|url=https://books.google.com/books?id=nPR1L4K5HuEC&pg=PA21|year=1994|publisher=Oxford University Press|isbn=978-0-19-506739-2|pages=21–}}{{cite book | vauthors = Maximov PY, McDaniel RE, Jordan VC |title=Tamoxifen: Pioneering Medicine in Breast Cancer|url=https://books.google.com/books?id=p-W5BAAAQBAJ&pg=PA7|date=23 July 2013|publisher=Springer Science & Business Media|isbn=978-3-0348-0664-0|pages=7–}}{{cite book| vauthors = Ravina E |title=The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs|url=https://books.google.com/books?id=iDNy0XxGqT8C&pg=PA177|date=11 January 2011|publisher=John Wiley & Sons|isbn=978-3-527-32669-3|pages=177–178}} Initially, [[clomifene]] was synthesized, and tamoxifen was developed subsequently. Tamoxifen is closely related structurally to other triphenylethylenes, such as clomifene, [[nafoxidine]], [[ospemifene]], [[toremifene]], and numerous others.{{cite book| vauthors = Cano A, Calaf i Alsina J, Duenas-Diez JL |title=Selective Estrogen Receptor Modulators: A New Brand of Multitarget Drugs|url=https://books.google.com/books?id=heJDAAAAQBAJ&pg=PA52|date=22 September 2006|publisher=Springer Science & Business Media|isbn=978-3-540-34742-2|pages=52–}}{{cite book| vauthors = Orwoll ES, Bilezikian JP, Vanderschueren D |title=Osteoporosis in Men: The Effects of Gender on Skeletal Health|url=https://books.google.com/books?id=nfWNYFdOsCsC&pg=PA717|date=30 November 2009|publisher=Academic Press|isbn=978-0-08-092346-8|pages=717–}} Other SERMs, like [[raloxifene]], are structurally distinct from tamoxifen and other triphenylethylenes. [247] => [248] => ==History== [249] => 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. 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.{{cite book | vauthors = Sneader W | title = Drug Discovery: A History | publisher = Wiley | location = New York | year = 2005 | isbn = 978-0-471-89979-2 | page = 472 pages }} [250] => [251] => 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.{{cite journal | vauthors = Quirke VM | 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 | date = 12 September 2017 | pmid = 28955226 | pmc = 5600945 | doi = 10.3389/fphar.2017.00620 | doi-access = free }} 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.{{cite journal | vauthors = Jordan VC | title = Tamoxifen: a most unlikely pioneering medicine | journal = Nature Reviews. Drug Discovery | volume = 2 | issue = 3 | pages = 205–213 | date = March 2003 | pmid = 12612646 | doi = 10.1038/nrd1031 | s2cid = 31333174 }} 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. 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. [252] => [253] => 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.{{cite web | url = https://www.usatoday.com/news/health/2002-07-24-cover-cancer_x.htm | title = Dog's tale of survival opens door in cancer research | vauthors = Kirk E | date = 24 July 2002 | work = Health and Behavior | publisher = USA Today | 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 | url-status = live }} 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.{{cite journal | vauthors = Blackwell KL, Haroon ZA, Shan S, Saito W, Broadwater G, Greenberg CS, Dewhirst MW | title = Tamoxifen inhibits angiogenesis in estrogen receptor-negative animal models | journal = Clinical Cancer Research | volume = 6 | issue = 11 | pages = 4359–4364 | date = November 2000 | pmid = 11106254 | url = http://clincancerres.aacrjournals.org/cgi/content/abstract/6/11/4359 | url-status = live | author7-link = Mark Dewhirst | archive-url = https://web.archive.org/web/20080906195254/http://clincancerres.aacrjournals.org/cgi/content/abstract/6/11/4359 | archive-date = 6 September 2008 }} [254] => [255] => 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.{{cite book| vauthors = Howell A, Jordan VC |chapter=Adjuvant Antihormone Therapy|year=2013|pages=229–254|doi=10.1142/9781848169586_0010| veditors = Jordon VC |title=Estrogen Action, Selective Estrogen Receptor Modulators And Women's Health: Progress And Promise|publisher=World Scientific|isbn=978-1-84816-959-3|chapter-url=https://books.google.com/books?id=ZM26CgAAQBAJ&pg=PA229}} 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.{{cite journal | vauthors = Cole MP, Jones CT, Todd ID | 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 | date = June 1971 | pmid = 5115829 | pmc = 2008453 | doi = 10.1038/bjc.1971.33 }} 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. Tamoxifen's further development may have been bolstered by a second clinical study by Harold W.C. Ward {{cite journal | vauthors = Ward HW | 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 | date = January 1973 | pmid = 4567104 | pmc = 1588574 | doi = 10.1136/bmj.1.5844.13 }} 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. 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.{{cite web |url=http://www.yorkshirepost.co.uk/news/features/maverick-and-pioneer-whose-work-is-improving-odds-in-breast-cancer-fight-1-5799838 |title=Maverick and pioneer whose work is improving odds in breast cancer fight |access-date=5 November 2013 |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 }}{{Cite news|url=http://www.yorkshirepost.co.uk/news/analysis/maverick-and-pioneer-whose-work-is-improving-odds-in-breast-cancer-fight-1-5799838|title=Maverick and pioneer whose work is improving odds in breast cancer fight|date=27 June 2013|work=The Yorkshire Post|access-date=7 April 2017|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|url-status=live}} 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. [256] => [257] => {{Comparison of early clinical experience with antiestrogens for advanced breast cancer}} [258] => [259] => 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.{{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 | display-authors = 6 | title = Improved survival among patients treated with adjuvant tamoxifen after mastectomy for early breast cancer | journal = Lancet | volume = 2 | issue = 8347 | pages = 450 | date = August 1983 | pmid = 6135926 | doi = 10.1016/S0140-6736(83)90406-3 | s2cid = 54230182 }} 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.{{cite journal | vauthors = Furr BJ, Jordan VC | title = The pharmacology and clinical uses of tamoxifen | journal = Pharmacology & Therapeutics | volume = 25 | issue = 2 | pages = 127–205 | year = 1984 | pmid = 6438654 | doi = 10.1016/0163-7258(84)90043-3 }} Nevertheless, tamoxifen had a relatively mild side-effect profile, and a number of large trials continued. [260] => [261] => The pharmacology of SERMs was discovered, defined, and deciphered during the 1980s.{{cite journal | vauthors = Jordan VC | title = Selective estrogen receptor modulation: a personal perspective | journal = Cancer Research | volume = 61 | issue = 15 | pages = 5683–5687 | date = August 2001 | pmid = 11479197 }} A clinical strategy was described{{cite journal | vauthors = Lerner LJ, Jordan VC | 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 | date = July 1990 | pmid = 2194650 }} 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. This story is told in: V. Craig Jordan, ed. 2013. "Estrogen Action, Selective Estrogen Receptor Modulators and Women's Health" Imperial College Press, Singapore. [262] => [263] => 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. It is by giving voice to cancer patients using tamoxifen, and so helping to push it forward, by justifying it both morally and scientifically to corporations. [264] => [265] => 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.{{cite journal | author = Early Breast Cancer Trialists' Collaborative Group | title = Tamoxifen for early breast cancer: an overview of the randomised trials. | journal = Lancet | volume = 351 | issue = 9114 | pages = 1451–1467 | date = May 1998 | pmid = 9605801 | doi = 10.1016/S0140-6736(97)11423-4 | s2cid = 46287542 }} [266] => [267] => ==Society and culture== [268] => [269] => ===Brand names=== [270] => Tamoxifen is marketed under the brand names Nolvadex and Soltamox, and a variety of other brand names throughout the world.{{Cite web | url=https://www.drugs.com/international/tamoxifen.html |title = Tamoxifen}} [271] => [272] => ===Economics=== [273] => Global sales of tamoxifen in 2001 were approximately $1.02 billion.{{cite web| url =http://www.bioportfolio.com/news/datamonitor_16.htm| title =Cancer the generic impact| publisher =BioPortfolio Limited| 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| url-status =dead}} 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.{{cite web| url =http://www.astrazeneca.com/_mshost3690701/content/resources/media/investors/2004-abr-brent-vose-oncology.pdf| title =AstraZenecain Cancer: Slide #15| vauthors = Vose B | work =AstraZeneca Annual Business Review| publisher =www.astrazeneca.com| 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| quote =2004 tamoxifen market share: 70% Source: IMS HEALTH, IMS MIDAS Monthly. July 2004. Aromatase Inhibitors + Tamoxifen| access-date =28 March 2009| url-status =live}} [274] => [275] => ==Research== [276] => 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).{{cite journal | vauthors = Eugster EA, Shankar R, Feezle LK, Pescovitz OH | 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 | year = 1999 | pmid = 10703542 | doi = 10.1515/jpem.1999.12.5.681 | s2cid = 71034635 }}{{cite journal | vauthors = Eugster EA, Rubin SD, Reiter EO, Plourde P, Jou HC, Pescovitz OH | 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 | date = July 2003 | pmid = 12915825 | doi = 10.1016/S0022-3476(03)00128-8 }} The same effects have also been seen in short pubertal boys.{{cite journal | vauthors = Kreher NC, Eugster EA, Shankar RR | title = The use of tamoxifen to improve height potential in short pubertal boys | journal = Pediatrics | volume = 116 | issue = 6 | pages = 1513–1515 | date = December 2005 | pmid = 16322179 | doi = 10.1542/peds.2005-0577 | s2cid = 45133251 }} 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.{{cite journal | vauthors = Karimian E, Chagin AS, Gjerde J, Heino T, Lien EA, Ohlsson C, Sävendahl L | 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 | date = August 2008 | pmid = 18348701 | doi = 10.1359/jbmr.080319 | s2cid = 35813153 | doi-access = free }}{{cite journal | vauthors = Chagin AS, Karimian E, Zaman F, Takigawa M, Chrysis D, Sävendahl L | 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 | date = May 2007 | pmid = 17293177 | doi = 10.1016/j.bone.2006.12.066 }} [277] => [278] => Tamoxifen has been studied in the treatment of the rare conditions of [[retroperitoneal fibrosis]]{{cite journal | vauthors = van Bommel EF, Hendriksz TR, Huiskes AW, Zeegers AG | title = Brief communication: tamoxifen therapy for nonmalignant retroperitoneal fibrosis | journal = Annals of Internal Medicine | volume = 144 | issue = 2 | pages = 101–106 | date = January 2006 | pmid = 16418409 | doi = 10.7326/0003-4819-144-2-200601170-00007 | s2cid = 25699557 }} and [[idiopathic sclerosing mesenteritis]].{{cite journal | vauthors = Akram S, Pardi DS, Schaffner JA, Smyrk TC | 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 | date = May 2007 | pmid = 17478346 | doi = 10.1016/j.cgh.2007.02.032 | doi-access = free }} It has also been proposed as part of a treatment plan for [[Riedel's thyroiditis]].{{cite journal | vauthors = Dabelic N, Jukic T, Labar Z, Novosel SA, Matesa N, Kusic Z | title = Riedel's thyroiditis treated with tamoxifen | journal = Croatian Medical Journal | volume = 44 | issue = 2 | pages = 239–241 | date = April 2003 | pmid = 12698518 | url = http://www.cmj.hr/2003/44/2/12698518.pdf | url-status = live | archive-url = https://web.archive.org/web/20080910130853/http://www.cmj.hr/2003/44/2/12698518.pdf | archive-date = 10 September 2008 }} [279] => [280] => 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.{{cite journal | vauthors = Feil R, Brocard J, Mascrez B, LeMeur M, Metzger D, Chambon P | 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 | date = October 1996 | pmid = 8855277 | pmc = 38252 | doi = 10.1073/pnas.93.20.10887 | doi-access = free | bibcode = 1996PNAS...9310887F }} 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. [281] => [282] => Tamoxifen may be effective in the treatment of [[mania]] in people with [[bipolar disorder]].{{cite journal | vauthors = Talaei A, Pourgholami M, Khatibi-Moghadam H, Faridhosseini F, Farhoudi F, Askari-Noghani A, Sadeghi R | 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 | date = June 2016 | pmid = 27088436 | doi = 10.1097/JCP.0000000000000492 | s2cid = 39792641 }} This is thought to be due to blockade of [[protein kinase C]] (PKC), an [[enzyme]] that regulates [[neuron]] activity in the [[brain]].{{cite journal | vauthors = Saxena A, Scaini G, Bavaresco DV, Leite C, Valvassori SS, Carvalho AF, Quevedo J | 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 | date = November 2017 | pmid = 29230399 | pmc = 5701269 | doi = 10.1159/000480349 }} Researchers believe PKC is overactive during the mania in bipolar patients. {{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.{{Cite web | url=https://adisinsight.springer.com/drugs/800036114 | title=Endoxifen - Intas Pharmaceuticals/Jina pharmaceuticals | work = AdisInsight | publisher = Springer Nature Switzerland AG }}{{cite journal | vauthors = Ahmad I | 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 | date = January 2018 | pmid = 29207335 | doi = 10.1016/j.ejmech.2017.11.056 }} [283] => [284] => == References == [285] => {{Reflist}} [286] => [287] => == Further reading == [288] => * {{cite book | title=Medical Genetics Summaries | chapter=Tamoxifen Therapy and CYP2D6 Genotype | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK247013/ | veditors=Pratt VM, McLeod HL, Rubinstein WS, Scott SA, Dean LC, Kattman BL, Malheiro AJ | display-editors=3 | publisher=[[National Center for Biotechnology Information]] (NCBI) | year=2014 | pmid=28520357 | id=Bookshelf ID: NBK247013 | vauthors=Dean L | url=https://www.ncbi.nlm.nih.gov/books/NBK61999/ }} [289] => [290] => == External links == [291] => * {{cite web| url = https://druginfo.nlm.nih.gov/drugportal/name/tamoxifen | publisher = U.S. National Library of Medicine| work = Drug Information Portal | title = Tamoxifen }} [292] => * {{cite web| url = https://druginfo.nlm.nih.gov/drugportal/name/tamoxifen%20citrate | publisher = U.S. National Library of Medicine| work = Drug Information Portal | title = Tamoxifen citrate }} [293] => * {{cite web | title=Tamoxifen citrate | website=National Cancer Institute | date=5 October 2006 | url=https://www.cancer.gov/about-cancer/treatment/drugs/tamoxifencitrate }} [294] => [295] => {{Estrogens and antiestrogens}} [296] => {{Estrogen receptor modulators}} [297] => {{AstraZeneca}} [298] => {{Portal bar | Medicine}} [299] => [300] => [[Category:Aromatase inhibitors]] [301] => [[Category:Drugs developed by AstraZeneca]] [302] => [[Category:Chemopreventive agents]] [303] => [[Category:Dimethylamino compounds]] [304] => [[Category:Glycine receptor agonists]] [305] => [[Category:GPER agonists]] [306] => [[Category:Hepatotoxins]] [307] => [[Category:Hormonal antineoplastic drugs]] [308] => [[Category:IARC Group 1 carcinogens]] [309] => [[Category:Mood stabilizers]] [310] => [[Category:Phenol ethers]] [311] => [[Category:Prodrugs]] [312] => [[Category:Progonadotropins]] [313] => [[Category:Selective estrogen receptor modulators]] [314] => [[Category:Triphenylethylenes]] [315] => [[Category:Wikipedia medicine articles ready to translate]] [316] => [[Category:Orphan drugs]] [] => )
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Tamoxifen

Tamoxifen is a medication widely used in the treatment and prevention of breast cancer. It belongs to a class of drugs called selective estrogen receptor modulators (SERMs), which interact with estrogen receptors in various tissues.

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It belongs to a class of drugs called selective estrogen receptor modulators (SERMs), which interact with estrogen receptors in various tissues. The Wikipedia page on tamoxifen provides detailed information on its mechanism of action, pharmacokinetics, and therapeutic uses. Tamoxifen works by competitively binding to estrogen receptors, blocking the estrogen hormone from binding to these receptors. This prevents the growth and division of estrogen-responsive breast cancer cells. The page also discusses the history of tamoxifen, from its discovery in the 1960s until its approval by regulatory agencies for the treatment of breast cancer. It highlights the significant impact of tamoxifen in improving the prognosis and survival rates of breast cancer patients. In addition to its role in the treatment of breast cancer, tamoxifen has been employed in the prevention of breast cancer in high-risk individuals and for the management of other hormone-sensitive cancers, such as endometrial and ovarian cancer. The page outlines the dosage, administration, and potential side effects of tamoxifen, as well as its interactions with other medications. Furthermore, the Wikipedia page touches upon ongoing research and developments related to tamoxifen, including studies on its long-term effects, its use in male breast cancer, and its potential applications in other types of cancers. Overall, the Wikipedia page on tamoxifen provides a comprehensive overview of this medication, detailing its history, mode of action, uses, and potential risks. It serves as a valuable resource for individuals seeking general information about tamoxifen or looking for a more in-depth understanding of its therapeutic applications in the treatment and prevention of breast cancer.

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