| Revision as of 19:11, 6 August 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,045 edits Script assisted update of identifiers for the Chem/Drugbox validation project (updated: 'ChEBI').← Previous edit |
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{{Short description|Chemical compound}} |
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{{refimprove|date=October 2010}} |
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{{Use dmy dates|date=February 2024}} |
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{{drugbox |
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{{cs1 config |name-list-style=vanc |display-authors=6}} |
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| Watchedfields = changed |
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{{Drugbox |
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| verifiedrevid = 422301461 |
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| Verifiedfields = verified |
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| IUPAC_name = 2,2'-bis(2-methylpropanenitrile)<ref></ref> |
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| Watchedfields = verified |
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| verifiedrevid = 443389404 |
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| image = Anastrozole.svg |
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| image = Anastrozole.svg |
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| image_class = skin-invert-image |
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| width = 225 |
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| alt = |
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| image2 = Anastrozole-from-xtal-3D-balls.png |
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| image2 = Anastrozole-from-xtal-3D-balls.png |
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| width2 = 225 |
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| CASNo_Ref = {{cascite|correct|CAS}} |
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| alt2 = |
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<!-- Clinical data --> |
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| tradename = Arimidex, Aremed, others<ref name="Drugs.com" /> |
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| Drugs.com = {{drugs.com|monograph|anastrozole}} |
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| MedlinePlus = a696018 |
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| DailyMedID = Anastrozole |
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| pregnancy_AU = C |
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| routes_of_administration = ] |
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| class = ]; ] |
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| ATC_prefix = L02 |
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| ATC_suffix = BG03 |
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| ATC_supplemental = |
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| legal_AU = S4 |
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| legal_UK = POM |
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| legal_US = Rx-only |
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<!-- Pharmacokinetic data --> |
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| bioavailability = Unknown (but well-absorbed in animals)<ref name="Lønning2003" /> |
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| protein_bound = 40%<ref name="Lonning2003" /><ref name="SanfordPlosker2008" /> |
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| metabolism = ] (~85%) (], ], ])<ref name="Lonning2003" /><ref name="Lønning2003" /><ref name="SanfordPlosker2008" /> |
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| metabolites = |
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| elimination_half-life = 40–50 hours<ref name="Lonning2003" /><ref name="Lønning2003" /><ref name="SanfordPlosker2008" /> |
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| excretion = ] (11%)<ref name="Lonning2003" /><ref name="Lønning2003" /><ref name="SanfordPlosker2008" /> |
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<!-- Identifiers --> |
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| CAS_number_Ref = {{cascite|correct|CAS}} |
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| CAS_number = 120511-73-1 |
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| PubChem = 2187 |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| DrugBank = DB01217 |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID = 2102 |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| UNII = 2Z07MYW1AZ |
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| UNII = 2Z07MYW1AZ |
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| KEGG_Ref = {{keggcite|correct|kegg}} |
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| KEGG_Ref = {{keggcite|correct|kegg}} |
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| KEGG = D00960 |
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| KEGG = D00960 |
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| ChEBI_Ref = {{ebicite|correct|EBI}} |
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| InChI = 1/C17H19N5/c1-16(2,9-18)14-5-13(8-22-12-20-11-21-22)6-15(7-14)17(3,4)10-19/h5-7,11-12H,8H2,1-4H3 |
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| ChEBI = 2704 |
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| InChIKey = YBBLVLTVTVSKRW-UHFFFAOYAZ |
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| smiles1 = CC(C)(C#N)c1cc(cc(c1)C(C)(C)C#N)Cn2cncn2 |
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| ChEMBL_Ref = {{ebicite|correct|EBI}} |
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| ChEMBL_Ref = {{ebicite|correct|EBI}} |
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| ChEMBL = 1399 |
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| ChEMBL = 1399 |
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| IUPHAR_ligand = 5137 |
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| synonyms = Anastrazole; anastrozol; ICI-D1033; ZD-1033 |
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<!-- Chemical data --> |
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| IUPAC_name = 2,2'-bis(2-methylpropanenitrile)<ref name="urlanastrozole (CHEBI:2704)">{{cite web | url = http://www.ebi.ac.uk/chebi/advancedSearchFT.do?searchString=anastrozole&queryBean.stars=3&queryBean.stars=-1 | title = anastrozole | work = Chemical Entities of Biological Interest (ChEBI) | publisher = European Molecular Biology Laboratory | access-date = 14 August 2011 | url-status = live | archive-url = https://web.archive.org/web/20110922050119/http://www.ebi.ac.uk/chebi/advancedSearchFT.do?searchString=anastrozole&queryBean.stars=3&queryBean.stars=-1 | archive-date = 22 September 2011 }}</ref> |
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| C=17 | H=19 | N=5 |
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| SMILES = N#CC(C)(C)c1cc(Cn2cncn2)cc(c1)C(C)(C)C#N |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI = 1S/C17H19N5/c1-16(2,9-18)14-5-13(8-22-12-20-11-21-22)6-15(7-14)17(3,4)10-19/h5-7,11-12H,8H2,1-4H3 |
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| StdInChI = 1S/C17H19N5/c1-16(2,9-18)14-5-13(8-22-12-20-11-21-22)6-15(7-14)17(3,4)10-19/h5-7,11-12H,8H2,1-4H3 |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey = YBBLVLTVTVSKRW-UHFFFAOYSA-N |
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| StdInChIKey = YBBLVLTVTVSKRW-UHFFFAOYSA-N |
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| CAS_number = 120511-73-1 |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID = 2102 |
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| ATC_prefix = L02 |
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| ATC_suffix = BG03 |
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| ATC_supplemental = |
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| ChEBI = 2704 |
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| PubChem = 2187 |
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| DrugBank = APRD00016 |
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| C = 17 | H = 19 | N = 5 |
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| molecular_weight = 293.366 g/mol |
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| smiles = N#CC(c1cc(cc(c1)C(C#N)(C)C)Cn2ncnc2)(C)C |
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| bioavailability = 83-85% |
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| protein_bound = 40% |
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| metabolism = 85% hepatic |
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| excretion = 11% renal |
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| elimination_half-life = 46.8 h<ref name="gyno"></ref> |
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| pregnancy_us = D |
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| pregnancy_category = D (U.S.) |
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| legal_status = Rx only (U.S.) |
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| routes_of_administration = oral |
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| licence_US = Anastrozole |
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}} |
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}} |
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<!-- Definition and medical uses --> |
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'''Anastrozole''' (]) marketed under the trade name '''Arimidex''' by ], is a drug used to treat ] after surgery and for metastases in both pre and post-] women. Anastrozole is an ], which means that it interrupts a critical step in the body's synthesis of estrogen. Some breast cancer cells require estrogen to grow, and eliminating estrogen suppresses their growth. Annual sales approx $2.2bn. The first patent for Arimidex expired in June 2010. Although this patent was originally set to expire in December 2009, the manufacturer was given a six-month extension for performing pediatric studies.<ref></ref> |
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'''Anastrozole''', sold under the brand name '''Arimidex''' among others, is an ]ic medication used in addition to other treatments for ].<ref name=Label2018>{{cite web |title=Highlights of Prescribing Information Anastrozole |url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/020541s031lbl.pdf |website=FDA |access-date=31 July 2019}}</ref><ref name=AHFS2016/> Specifically it is used for ] breast cancer.<ref name=AHFS2016/> It has also been used to prevent breast cancer in those at high risk.<ref name=AHFS2016/> It is taken ].<ref name=AHFS2016>{{cite web|title=Anastrozole|url=https://www.drugs.com/monograph/anastrozole.html|publisher=The American Society of Health-System Pharmacists|access-date=8 December 2016|url-status=live|archive-url=https://web.archive.org/web/20161221013418/https://www.drugs.com/monograph/anastrozole.html|archive-date=21 December 2016}}</ref> |
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<!-- Side effects and mechanism --> |
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==Clinical trials== |
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Common side effects of anastrozole include ]es, ], ], and ].<ref name=AHFS2016/><ref name=Label2018/> Severe side effects include an increased risk of ] and ].<ref name=AHFS2016/> Use during ] may harm the baby.<ref name=AHFS2016/> Anastrozole is in the ] family of medications.<ref name=AHFS2016/> It works by blocking the ] of ]s in the body, and hence has ]ic effects.<ref name=AHFS2016/> |
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The ATAC (Arimidex, ], Alone or in Combination) trial was an international randomised controlled trial of 9366 women with localized ] who received either anastrozole, ], or both for five years, followed by five years of follow-up.<ref name="ATAC">{{cite journal |author=Howell A, Cuzick J, ], ''et al.'' |title=Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer |journal=] |volume=365 |issue=9453 |pages=60–2 |year=2005 |pmid=15639680 |doi=10.1016/S0140-6736(04)17666-6}}</ref> After more than 5 years the group that received anastrozole had significantly better clinical results than the tamoxifen group.<ref name="ATAC"/> The trial suggested that anastrozole is the preferred medical therapy for postmenopausal women with localized breast cancer that is ] (ER) positive.<ref name="ATAC"/> Another study found that the risk of recurrence was reduced 40% (with some risk of bone fracture) and that ER negative patients also benefited from switching to Arimidex.<ref name="Jakesz">http://www.breastcancer.org/treatment/hormonal/new_research/20051003.jsp Review of: Arimidex After Two Years of Tamoxifen Reduces Recurrence in Post-Menopausal Women. R. Jakesz et al., The Lancet, August 6, 2005</ref> |
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<!-- History and culture --> |
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==Mechanism of action== |
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Anastrozole was patented in 1987 and was approved for medical use in 1995.<ref name=Fis2006>{{cite book| vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery|date=2006|publisher=John Wiley & Sons|isbn=9783527607495|page=516|url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA516|language=en|url-status=live|archive-url=https://web.archive.org/web/20161220163842/https://books.google.ca/books?id=FjKfqkaKkAAC&pg=PA516|archive-date=20 December 2016}}</ref><ref name=Dukes1997>{{cite journal | vauthors = Dukes M | title = The relevance of preclinical models to the treatment of postmenopausal breast cancer | journal = Oncology | volume = 54 | issue = 2 | pages = 6–10 | date = 1997 | pmid = 9394853 | doi = 10.1159/000227748 }}</ref> It is on the ].<ref name="WHO21st">{{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 }}</ref> Anastrozole is available as a ].<ref name=AHFS2016/> In 2022, it was the 179th most commonly prescribed medication in the United States, with more than 2{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2022 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=30 August 2024 | archive-date=30 August 2024 | archive-url=https://web.archive.org/web/20240830202410/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Anastrozole Drug Usage Statistics, United States, 2013 - 2022 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Anastrozole | access-date = 30 August 2024 }}</ref> |
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Anastrozole inhibits the enzyme ], which is responsible for converting ]s to ]s in peripheral tissues.<ref>{{cite journal |author=Simpson ER |title=Sources of estrogen and their importance |journal=The Journal of Steroid Biochemistry and Molecular Biology |volume=86 |issue=3–5 |pages=225–30 |year=2003 |pmid=14623515 |doi=10.1016/S0960-0760(03)00360-1}}</ref> Anastrozole binds reversibly to the aromatase enzyme through ]. Elevated levels of estrogens may increase the severity of breast cancer, as sex hormones can cause ] and ] at estrogen receptor sites.{{Citation needed|date=October 2010}} |
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==Medical uses== |
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===Breast cancer=== |
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Anastrozole is used in the treatment and prevention of ] in women.<ref name="AHFS2016" /> The '''A'''rimidex, '''T'''amoxifen, '''A'''lone or in '''C'''ombination (ATAC) trial was of ] and women received either anastrozole, the ] ], or both for five years, followed by five years of follow-up.<ref name="ATAC">{{cite journal | vauthors = Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF, Hoctin-Boes G, Houghton J, Locker GY, Tobias JS | title = Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer | journal = Lancet | volume = 365 | issue = 9453 | pages = 60–62 | year = 2005 | pmid = 15639680 | doi = 10.1016/S0140-6736(04)17666-6 | s2cid = 8350282 | author3-link = Michael Baum (surgeon) }} {{primary-inline|date=June 2018}}</ref> After more than 5 years the group that received anastrozole had better results than the tamoxifen group.<ref name="ATAC"/> The trial suggested that anastrozole is the preferred medical therapy for ] women with localized ]-positive breast cancer.<ref name="ATAC"/> |
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===Early puberty=== |
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Anastrozole is used at a dosage of 0.5 to 1 mg/day in combination with the ] ] in the treatment of ], for instance due to ] (testotoxicosis) and ], in boys.<ref name="FDALabel">{{cite web |title=Casodex® (bicalutamide) Tablets |publisher=FDA |url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020498s028lbl.pdf |url-status=live |archive-url=https://web.archive.org/web/20190730062812/https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020498s028lbl.pdf |archive-date=30 July 2019 }}</ref><ref name="SchoelwerEugster2015">{{cite book | vauthors = Schoelwer M, Eugster EA | title = Puberty from Bench to Clinic | chapter = Treatment of Peripheral Precocious Puberty | volume = 29 | pages = 230–9 | year = 2015 | pmid = 26680582 | pmc = 5345994 | doi = 10.1159/000438895 | isbn = 978-3-318-02788-4 | series = Endocrine Development }}</ref><ref name="pmid31144045">{{cite book | vauthors = Zacharin M | chapter = Disorders of Puberty: Pharmacotherapeutic Strategies for Management|title= Pediatric Pharmacotherapy| series = Handbook of Experimental Pharmacology | volume = 261 | pages = 507–538 | date = May 2019 | publisher = Springer| pmid = 31144045 | doi = 10.1007/164_2019_208 | isbn = 978-3-030-50493-9 | s2cid = 169040406 }}</ref><ref name="KliegmanStanton2015">{{cite book | vauthors = Kliegman RM, Stanton B, St Geme J, Schor NF |title=Nelson Textbook of Pediatrics |url=https://books.google.com/books?id=P9piCAAAQBAJ&pg=PA2661 |date=17 April 2015 |publisher=Elsevier Health Sciences |isbn=978-0-323-26352-8 |pages=2661–}}</ref><ref name="pmid29292624">{{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 }}</ref><ref name="HaddadEugster2012">{{cite book| vauthors = Haddad NG, Eugster EA |title=Handbook of Growth and Growth Monitoring in Health and Disease |chapter=Peripheral Precocious Puberty: Interventions to Improve Growth|year=2012|pages=1199–1212|publisher=Springer |doi=10.1007/978-1-4419-1795-9_71|isbn=978-1-4419-1794-2}}</ref><ref name="HaddadEugster2019">{{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 }}</ref><ref name="MisraRadovick2018">{{cite book| vauthors = Misra M, Radovick S |title=Pediatric Endocrinology |chapter=Precocious Puberty|year=2018|pages=589–615|publisher=Springer |doi=10.1007/978-3-319-73782-9_26|isbn=978-3-319-73781-2}}</ref><ref name="Mauras2011">{{cite journal | vauthors = Mauras N | title = Strategies for maximizing growth in puberty in children with short stature | journal = Pediatric Clinics of North America | volume = 58 | issue = 5 | pages = 1167–79, x | date = October 2011 | pmid = 21981954 | doi = 10.1016/j.pcl.2011.07.007 }}</ref><ref name="Fuqua2013">{{cite journal | vauthors = Fuqua JS | title = Treatment and outcomes of precocious puberty: an update | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 98 | issue = 6 | pages = 2198–2207 | date = June 2013 | pmid = 23515450 | doi = 10.1210/jc.2013-1024 | doi-access = free }}</ref> |
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===Available forms=== |
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Anastrozole is available in the form of 1 mg ] ]s.<ref name=Label2018 /><ref name="WhiteBradnam2015">{{cite book| vauthors = White R, Bradnam V |title=Handbook of Drug Administration via Enteral Feeding Tubes, 3rd edition|url=https://books.google.com/books?id=yyikBwAAQBAJ&pg=PA108|date=11 March 2015|publisher=Pharmaceutical Press|isbn=978-0-85711-162-3|pages=108–}}</ref> No alternative ]s or ] are available.<ref name="WhiteBradnam2015" /> |
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==Contraindications== |
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]s of anastrozole include ] to anastrozole or any other component of anastrozole formulations, ], and ].<ref name=Label2018 /> Hypersensitivity reactions to anastrozole including ], ], and ] have been observed.<ref name=Label2018 /> |
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==Side effects== |
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==Side effects== |
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Common ]s of anastrozole (≥10% incidence) include ]es, |
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Bone weakness has been associated with anastrozole. Women who switched to anastrozole after two years on tamoxifen reported twice as many fractures as those who continued to take tamoxifen (2.1% compared to 1%).<ref name="Jakesz"/> ] are sometimes prescribed to prevent the osteoporosis induced by aromatase inhibitors but have another serious side effect, ]. Since ] have a bone strengthening effect,<ref>Rejnmark L, Vestergaard P, Mosekilde L. Statin but not nonstatin lipid-lowering drugs decrease fracture risk: a nationwide case-control study. Calcif Tissue Int 2006; 79:27–36 </ref> combining a statin with an aromatase inhibitor may avoid both fractures and possible cardiovascular risks<ref>Ewer MS, Glück S. A woman's heart: the impact of adjuvant endocrine therapy on cardiovascular health. Cancer. 2009 May 1;115(9):1813-26,</ref> without jaw osteonecrosis.<ref>Lehrer, S. Statin use to prevent aromatase inhibitor-induced fracture and cardiovascular complications. Med Hypotheses. 2007;68(6)1417. Epub 2006 Dec 29.</ref> In one study of women with breast cancer taking anastrozole, statin use was associated with a 38% reduced fracture risk, or about the equivalent of 10 mg ] daily.<ref>R. Eastell. Risk factors for fracture: 5-year results of the 'arimidex' (anastrozole), tamoxifen, alone or in combination (ATAC) trial. 33rd European Calcified Tissue Symposium 2006. abstract OC008. Calcif Tissue Int (2006) 78(Suppl 1):S27.</ref> |
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], ], ], ], ], ], ] and ], ], ], ]s, ], ], ], ], ], ], ], ], and ].<ref name=Label2018 /> Serious but rare adverse effects (<0.1% incidence) include ]s such as ]s, ]s, or ]s; ]s with ] of the ], ], ], and/or ] that may cause difficulty ] or ]; and ] as well as ].<ref name=Label2018 /> |
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==Usage in men== |
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== Interactions == |
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While officially indicated for women, this drug has proven effective in the off-label use of reducing estrogens (in particular and more importantly, estradiol) in men.<ref name="Steroid"></ref> Excess estradiol in men can cause ], ], and symptoms of ].<ref></ref> It can also contribute to increased risk of stroke, heart attack, chronic inflammation, prostate enlargement and prostate cancer.<ref>Faloon, William. "Dangers of Excess Estrogen In the Aging Male". Life Extension Magazine, November 2008. </ref> Some ] and ] will also use anastrozole as a part of their ] to reduce and prevent symptoms of excess estrogens; in particular, ] and water retention.<ref name="Steroid"/> Study data currently suggest that dosages of 0.5 mg to 1 mg a day reduce serum estradiol by about 50% in men, which differs from the typical reduction in postmenopausal women.<ref></ref> However the reduction may be different for men with grossly elevated estradiol (clinical data are currently lacking).{{Citation needed|date=October 2010}} |
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Anastrozole is thought to have clinically negligible inhibitory effects on the ] ]s ], ], ], ], ], and ].<ref name="Lonning2003" /><ref name="Lønning2003" /><ref name="SanfordPlosker2008" /><ref name=Label2018 /> As a result, it is thought that ]s of anastrozole with cytochrome P450 ]s are unlikely.<ref name="SanfordPlosker2008" /> No clinically significant ]s have been reported with anastrozole as of 2003.<ref name="Lonning2003" /> |
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==Usage in children== |
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This drug is frequently used in the treatment of children with ] to stop or slow the onset of puberty and in the treatment of moderate-to-severe pubertal gynecomastia.<ref name="growth"></ref><ref name="gyno"/> The cause of the growth disorder is through hormones which may trigger the early onset of puberty.{{Citation needed|date=October 2010}} At the onset of puberty the bone growth plates begin to close due to increased circulating ].<ref name="growth"/> Arimidex is shown to slow or stop this processes.<ref name="height"></ref> Arimidex has shown to increase the predicted adult height in adolescent males with ] deficiency treated with GH.<ref name="height"/> |
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Anastrozole does not affect circulating levels of ] or its major ] ''N''-desmethyltamoxifen.<ref name="Lonning2003" /><ref name="Lønning2003" /> However, tamoxifen has been found to decrease ] ] levels of anastrozole by 27%.<ref name="Lonning2003" /><ref name="Lønning2003" /> But estradiol levels were not significantly different in the group that received both anastrozole and tamoxifen compared to the anastrozole alone group, so the decrease in anastrozole levels is not thought to be clinically important.<ref name="SanfordPlosker2008" /> |
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==Pharmacology== |
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===Pharmacodynamics=== |
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Anastrozole works by ] binding to the ] ], and through ] blocks the conversion of ]s to ]s in peripheral (extragonadal) ].<ref name="pmid14623515">{{cite journal | vauthors = Simpson ER | title = Sources of estrogen and their importance | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 86 | issue = 3–5 | pages = 225–230 | date = September 2003 | pmid = 14623515 | doi = 10.1016/S0960-0760(03)00360-1 | s2cid = 11210435 }}</ref> The medication has been found to achieve 96.7% to 97.3% inhibition of aromatase at a dosage of 1 mg/day and 98.1% inhibition of aromatase at a dosage of 10 mg/day in humans.<ref name="Lonning2003">{{cite journal | vauthors = Lønning P, Pfister C, Martoni A, Zamagni C | title = Pharmacokinetics of third-generation aromatase inhibitors | journal = Seminars in Oncology | volume = 30 | issue = 4 Suppl 14 | pages = 23–32 | date = August 2003 | pmid = 14513434 | doi = 10.1016/S0093-7754(03)00305-1 }}</ref><ref name="Lønning2003">{{cite journal | vauthors = Lønning P | title = Clinical pharmacokinetics of aromatase inhibitors and inactivators | journal = Clinical Pharmacokinetics | volume = 42 | issue = 7 | pages = 619–631 | year = 2003 | pmid = 12844324 | doi = 10.2165/00003088-200342070-00002 | s2cid = 9585901 }}</ref> As such, 1 mg/day is considered to be the minimal dosage required to achieve maximal suppression of aromatase with anastrozole.<ref name="Lonning2003" /> This decrease in aromatase activity results in an at least 85% decrease in estradiol levels in postmenopausal women.<ref name="Lonning2003" /> Levels of ]s and other ]s are unaffected by anastrozole.<ref name="Lonning2003" /> |
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{{Pharmacodynamics of aromatase inhibitors}} |
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===Pharmacokinetics=== |
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The ] of anastrozole in humans is unknown, but it was found to be ] in animals.<ref name="Lønning2003" /><ref name=Label2018 /> Absorption of anastrozole is linear over a dosage range of 1 to 20 mg/day in humans and does not change with repeated administration.<ref name="Lonning2003" /><ref name="SanfordPlosker2008" /><ref name=Label2018 /> ] does not significantly influence the extent of absorption of anastrozole.<ref name="SanfordPlosker2008" /><ref name=Label2018 /> ] levels of anastrozole occur a median 3 hours after administration, but with a wide range of 2 to 12 hours.<ref name="Lønning2003" /><ref name="SanfordPlosker2008" /> ] levels of anastrozole are achieved within 7 to 10 days of continuous administration, with 3.5-fold accumulation.<ref name="Lonning2003" /><ref name="Lønning2003" /><ref name="SanfordPlosker2008" /> However, maximal suppression of estradiol levels occurs within 3 or 4 days of therapy.<ref name="Lonning2003" /> |
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Active ] of anastrozole by ] at the ] has been found to limit the ] penetration of anastrozole in rodents, whereas this was not the case with ] and ].<ref name="CostaCarneiro2016">{{cite journal | vauthors = Costa R, Carneiro BA, Wainwright DA, Santa-Maria CA, Kumthekar P, Chae YK, Gradishar WJ, Cristofanilli M, Giles FJ | title = Developmental therapeutics for patients with breast cancer and central nervous system metastasis: current landscape and future perspectives | journal = Annals of Oncology | volume = 28 | issue = 1 | pages = 44–56 | date = January 2017 | pmid = 28177431 | pmc = 7360139 | doi = 10.1093/annonc/mdw532 | doi-access = free }}</ref><ref name="RussellCheung2017">{{cite journal | vauthors = Russell N, Cheung A, Grossmann M | title = Estradiol for the mitigation of adverse effects of androgen deprivation therapy | journal = Endocrine-Related Cancer | volume = 24 | issue = 8 | pages = R297–R313 | date = August 2017 | pmid = 28667081 | doi = 10.1530/ERC-17-0153 | doi-access = free }}</ref><ref name="MiyajimaKusuhara2013">{{cite journal | vauthors = Miyajima M, Kusuhara H, Takahashi K, Takashima T, Hosoya T, Watanabe Y, Sugiyama Y | title = Investigation of the effect of active efflux at the blood-brain barrier on the distribution of nonsteroidal aromatase inhibitors in the central nervous system | journal = Journal of Pharmaceutical Sciences | volume = 102 | issue = 9 | pages = 3309–3319 | date = September 2013 | pmid = 23712697 | doi = 10.1002/jps.23600 | doi-access = free }}</ref> As such, anastrozole may have ] in humans, although this has yet to be confirmed.<ref name="MiyajimaKusuhara2013" /> In any case, estradiol is synthesized peripherally and readily crosses the blood–brain barrier, so anastrozole would still expected to reduce estradiol levels in the central nervous system to a certain degree. The ] of anastrozole is 40%.<ref name="Lonning2003" /><ref name="SanfordPlosker2008" /> |
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The ] of anastrozole is by ], ], and ].<ref name="Lonning2003" /> Inhibition of aromatase is due to anastrozole itself rather than to ]s, with the major circulating metabolite being inactive.<ref name=Label2018 /> The ] of anastrozole is 40 to 50 hours (1.7 to 2.1 days).<ref name="Lonning2003" /><ref name="Lønning2003" /><ref name="SanfordPlosker2008" /> This allows for convenient once-daily administration.<ref name="SanfordPlosker2008" /> The medication is ] predominantly by metabolism in the ] (83 to 85%) but also by residual ] by the ]s unchanged (11%).<ref name="Lonning2003" /><ref name="Lønning2003" /><ref name="SanfordPlosker2008" /> Anastrozole is excreted primarily in ] but also to a lesser extent in ].<ref name="SanfordPlosker2008" /> |
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==Chemistry== |
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==Chemistry== |
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Anastrozole is a ] ] ].<ref name="Lonning2003" /><ref name="SanfordPlosker2008">{{cite journal | vauthors = Sanford M, Plosker GL | title = Anastrozole: a review of its use in postmenopausal women with early-stage breast cancer | journal = Drugs | volume = 68 | issue = 9 | pages = 1319–1340 | year = 2008 | pmid = 18547136 | doi = 10.2165/00003495-200868090-00007 | s2cid = 195687223 }}</ref> It is also known as α,α,α',α'-tetramethyl-5-(1''H''-1,2,4-triazol-1-ylmethyl)-''m''-benzenediacetonitrile.<ref name="Drugs.com" /> Anastrozole is structurally related to ], ], and ], with all being classified as ]s.<ref name="Thurston2006">{{cite book| vauthors = Thurston DE |title=Chemistry and Pharmacology of Anticancer Drugs|url=https://books.google.com/books?id=6mPLBQAAQBAJ&pg=PA136|date=22 November 2006|publisher=CRC Press|isbn=978-1-4200-0890-6|pages=136–}}</ref><ref name="Kunal2015">{{cite book|author=Roy, Kunal|title=Quantitative Structure-Activity Relationships in Drug Design, Predictive Toxicology, and Risk Assessment|url=https://books.google.com/books?id=z-yfBwAAQBAJ&pg=PA437|date=28 February 2015|publisher=IGI Global|isbn=978-1-4666-8137-8|pages=437–}}</ref><ref name="SmithAllerton2012">{{cite book| vauthors = Smith DA, Allerton C, Kalgutkar AS, van de Waterbeemd H, Walker DK |title=Pharmacokinetics and Metabolism in Drug Design|url=https://books.google.com/books?id=tz6khNt2wSYC&pg=PA197|date=13 September 2012|publisher=John Wiley & Sons|isbn=978-3-527-64529-9|pages=197–}}</ref><ref>{{cite book|title=Environmental Health Perspectives: Supplements|url=https://books.google.com/books?id=HjL1IgWzy1gC|year=1993|publisher=U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Environmental Health Sciences|pages=256–260}}</ref> |
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==History== |
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The synthesis begins with nucleophilic substitution of two benzylic bromides in α,α'-dibromomesitylene (prepared by radical bromination of ], not shown on the scheme) with cyanide by treatment with potassium cyanide under ] conditions, affording the dinitrile.{{Citation needed|date=October 2010}} Exhaustive methylation with ] and ] leads to the replacement of the more acidic side chain ] atoms by ] groups.{{Citation needed|date=October 2010}} Treatment with ] in the presence of ] leads to the formation of the corresponding benzyl bromide.{{Citation needed|date=October 2010}} Reaction of that product with ] in the presence of a ] completes the synthesis of the ].{{Citation needed|date=October 2010}} |
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Anastrozole was patented by ] (ICI) in 1987 and was approved for medical use, specifically the treatment of breast cancer, in 1995.<ref name="Fis2006" /><ref name="Dukes1997" /> |
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==Society and culture== |
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===Generic names=== |
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{{US patent|4935437}} |
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''Anastrozole'' is the ] of the drug and its {{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|USAN|United States Adopted Name}}, {{abbrlink|BAN|British Approved Name}}, and {{abbrlink|JAN|Japanese Accepted Name}}.<ref name="Drugs.com" /> |
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==References== |
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===Brand names=== |
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Anastrozole is primarily sold under the brand name Arimidex.<ref name="Drugs.com">{{Cite web | url=https://www.drugs.com/international/anastrozole.html |title = Anastrozole}}</ref> However, it is also marketed under a variety of other brand names throughout the world.<ref name="Drugs.com" /> |
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{{reflist}} |
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==External links== |
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===Availability=== |
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Anastrozole is available widely throughout the world.<ref name="Drugs.com" /> |
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==Research== |
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Anastrozole is surprisingly ineffective at treating ], in contrast to ]s like ].<ref name="SungFagerlund2015">{{cite journal | vauthors = Fagerlund A, Cormio L, Palangi L, Lewin R, Santanelli di Pompeo F, Elander A, Selvaggi G | title = Gynecomastia in Patients with Prostate Cancer: A Systematic Review | journal = PLOS ONE | volume = 10 | issue = 8 | pages = e0136094 | year = 2015 | pmid = 26308532 | pmc = 4550398 | doi = 10.1371/journal.pone.0136094 | doi-access = free | bibcode = 2015PLoSO..1036094F }}</ref><ref name="BedognettiRubagotti2010">{{cite journal | vauthors = Bedognetti D, Rubagotti A, Zoppoli G, Boccardo F | title = Gynaecomastia: the anastrozole paradox | journal = Journal of Pediatric Endocrinology & Metabolism | volume = 23 | issue = 1–2 | pages = 205–206 | year = 2010 | pmid = 20432826 | doi = 10.1515/JPEM.2010.23.1-2.205 | s2cid = 41999854 }}</ref> |
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Anastrozole was under development for the treatment of ] but did not complete development and hence was never approved for this indication.<ref name="AdisInsight-1">{{cite web | title = Anastrozole - AstraZeneca | url = https://adisinsight.springer.com/drugs/800002571 | work = Adis Insight }}</ref> |
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{{Sex hormones}} |
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An anastrozole and ] ] (developmental code name BAY 98–7196) was under development for use as a ] and treatment for ], but development was discontinued in November 2018 and the formulation was never marketed.<ref name="AdisInsight-2">{{cite web | title = Anastrozole/levonorgestrel intravaginal ring - Bayer HealthCare | url = https://adisinsight.springer.com/drugs/800040286 | work = Adis Insight }}</ref> |
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Anastrozole increases ] levels in males and has been studied as an alternative method of ] in men with ].<ref name="SerefogluGokce2013">{{cite book| vauthors = Serefoglu EC, Gokce A, Hellstrom WJ, Guay AT |chapter=Alternate Therapies for Testosterone Replacement | title = Androgen Deficiency and Testosterone Replacement |series=Current Clinical Urology |year=2013|pages=141–147|publisher=Humana Press |doi=10.1007/978-1-62703-179-0_11|isbn=978-1-62703-178-3}}</ref><ref name="KheraAdaikan2016">{{cite journal | vauthors = Khera M, Adaikan G, Buvat J, Carrier S, El-Meliegy A, Hatzimouratidis K, McCullough A, Morgentaler A, Torres LO, Salonia A | title = Diagnosis and Treatment of Testosterone Deficiency: Recommendations From the Fourth International Consultation for Sexual Medicine (ICSM 2015) | journal = The Journal of Sexual Medicine | volume = 13 | issue = 12 | pages = 1787–1804 | date = December 2016 | pmid = 27914560 | doi = 10.1016/j.jsxm.2016.10.009 }}</ref> However, there are concerns about its long-term influence on ] in this patient population, as well as other adverse effects.<ref name="SerefogluGokce2013" /> |
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== References == |
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{{Reflist}} |
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{{Estrogens and antiestrogens}} |
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{{AstraZeneca}} |
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{{AstraZeneca}} |
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{{Portal bar | Medicine}} |
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{{Authority control}} |
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