Estradiol stearateのソースを表示

{{Short description|Chemical compound}}
{{Infobox drug
| Verifiedfields = 
| Watchedfields = 
| verifiedrevid = 
| IUPAC_name = [(8''R'',9''S'',13''S'',14''S'',17''S'')-3-Hydroxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[''a'']phenanthren-17-yl] octadecanoate
| image = Estradiol stearate structure.svg
| width = 250px

<!--Clinical data-->
| tradename = Depofollan
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_US = <!-- A / B / C / D / X -->
| pregnancy_category = 
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->
| legal_CA = 
| legal_UK = 
| legal_US = 
| legal_status = 
| routes_of_administration = [[Intramuscular injection]]
| class = [[Estrogen (medication)|Estrogen]]; [[Estrogen ester]]

<!--Pharmacokinetic data-->
| bioavailability = 
| protein_bound = 
| metabolism = 
| elimination_half-life = 
| excretion =

<!--Identifiers-->
| CAS_number_Ref = {{cascite|correct|CAS}}
| CAS_number = 82205-00-3
| CAS_supplemental = 
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII =59G2KR8QBG
| ATC_prefix = 
| ATC_suffix = 
| PubChem = 67100
| DrugBank_Ref = 
| DrugBank = 
| ChemSpiderID_Ref = 
| ChemSpiderID = 60448
| synonyms = E2-17-St; Estradiol octadecanoate; Estradiol 17β-stearate; Estradiol 17β-octadecanoate

<!--Chemical data-->
| C=36 | H=58 | N= | O=3
| SMILES = CCCCCCCCCCCCCCCCCC(=O)O[C@H]1CC[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@]12C
| StdInChI_Ref = 
| StdInChI = 1S/C36H58O3/c1-3-4-5-6-7-8-9-10-11-12-13-14-15-16-17-18-35(38)39-34-24-23-33-32-21-19-28-27-29(37)20-22-30(28)31(32)25-26-36(33,34)2/h20,22,27,31-34,37H,3-19,21,23-26H2,1-2H3/t31-,32-,33+,34+,36+/m1/s1
| StdInChIKey_Ref = 
| StdInChIKey = KIADYVOYCQRXRE-IMTRJTTHSA-N
}}

'''Estradiol stearate''' ('''E2-17-St'''), also known as '''estradiol octadecanoate''' and sold under the brand name '''Depofollan''', is a [[natural product|naturally occurring]] [[estrogen (medication)|estrogen]] and an [[estrogen ester]] – specifically, the C17β [[stearic acid|stearate]] [[ester]] of [[estradiol]].<ref name="Elks2014">{{cite book| vauthors = Elks J |title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=RA1-PA129|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|page=898}}</ref><ref name="IndexNominum2000">{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA405|date=January 2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=405–}}</ref><ref name="Negwer1987">{{cite book | vauthors = Negwer M |title=Organic-chemical Drugs and Their Synonyms: (an International Survey)|url=https://books.google.com/books?id=k6fwAAAAMAAJ|year=1987|publisher=VCH Publishers|isbn=978-0-89573-552-2|quote=Estra-1,3,5(10)-triene-3,173-diol 17-octadecanoate = 3,173-Estradiol 17-stearate = (173)-Estra-1,3,5- (10)-triene-3,17-diol 17-octadecanoate (e) S Depofollan, Estradiol stearate, Ostradiolstearat U Depot-estrogen 8103}}</ref><ref name="JosephyRadt1956">{{cite book| vauthors = Josephy E, Radt F |title=Elsevier's Encyclopædia of Organic Chemistry|url=https://books.google.com/books?id=3oeDq5LQ9bYC|year=1956|pages=1974–1976}}</ref><ref name="Hochberg_1990">{{cite journal | vauthors = Hochberg RB, Pahuja SL, Larner JM, Zielinski JE | title = Estradiol-fatty acid esters. Endogenous long-lived estrogens | journal = Annals of the New York Academy of Sciences | volume = 595 | issue = 1 | pages = 74–92 | year = 1990 | pmid = 2197972 | doi = 10.1111/j.1749-6632.1990.tb34284.x | s2cid = 19866729 | bibcode = 1990NYASA.595...74H }}</ref> It occurs in the body as a very long-lasting [[metabolite]] and [[prohormone]] of estradiol.<ref name="Hochberg_1990" /> The compound is one of the components that collectively constitute [[lipoidal estradiol]], another of which is [[estradiol palmitate]].<ref name="OettelSchillinger2012">{{cite book| vauthors = Oettel M, Schillinger E |title=Estrogens and Antiestrogens I: Physiology and Mechanisms of Action of Estrogens and Antiestrogens|url=https://books.google.com/books?id=0BfrCAAAQBAJ&pg=PA235|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-58616-3|pages=235–237}}</ref><ref name="Hochberg_1990" /> It is extremely [[lipophilic]] and [[hydrophobic]].<ref name="Hochberg_1990" /> Estradiol stearate has no [[affinity (pharmacology)|affinity]] for the [[estrogen receptor]], requiring [[biotransformation|transformation]] into estradiol via [[esterase]]s for its estrogenic activity.<ref name="pmid9626557" /><ref name="JanockoLarner1984">{{cite journal | vauthors = Janocko L, Larner JM, Hochberg RB | title = The interaction of C-17 esters of estradiol with the estrogen receptor | journal = Endocrinology | volume = 114 | issue = 4 | pages = 1180–1186 | date = April 1984 | pmid = 6705734 | doi = 10.1210/endo-114-4-1180 }}</ref><ref name="Vazquez-AlcantaraMenjivar1989">{{cite journal | vauthors = Vazquez-Alcantara MA, Menjivar M, Garcia GA, Díaz-Zagoya JC, Garza-Flores J | title = Long-acting estrogenic responses of estradiol fatty acid esters | journal = Journal of Steroid Biochemistry | volume = 33 | issue = 6 | pages = 1111–1118 | date = December 1989 | pmid = 2515394 | doi = 10.1016/0022-4731(89)90417-2 }}</ref><ref name="Hochberg_1990" /> The compound does not bind to [[sex hormone-binding globulin]] or [[α-fetoprotein]], instead being transported by [[lipoprotein]]s such as [[high-density lipoprotein]] and [[low-density lipoprotein]].<ref name="Hochberg_1990" />

Estradiol stearate has a prolonged duration of action relative to estradiol regardless of whether it is given by [[intravenous injection]] or [[subcutaneous injection]].<ref name="pmid9626557">{{cite journal | vauthors = Hochberg RB | title = Biological esterification of steroids | journal = Endocrine Reviews | volume = 19 | issue = 3 | pages = 331–348 | date = June 1998 | pmid = 9626557 | doi = 10.1210/edrv.19.3.0330 | doi-access = free }}</ref> This is in contrast to short-chain fatty acid esters of estradiol, such as [[estradiol benzoate]], which do not show a prolonged duration with intravenous injection.<ref name="pmid20781252">{{cite journal | vauthors = Parkes AS | title = Effective Absorption of Hormones | journal = British Medical Journal | volume = 1 | issue = 4024 | pages = 371–373 | date = February 1938 | pmid = 20781252 | pmc = 2085798 | doi = 10.1136/bmj.1.4024.371 }}</ref> When administered by intravenous injection in rodents, estradiol stearate has a greatly increased [[terminal half-life]] relative to estradiol (6&nbsp;hours vs. 2&nbsp;minutes).<ref name="pmid9626557" /> Estradiol stearate also had a half-life that was 60% longer than that of estradiol arachidonate, despite similar ester chain lengths.<ref name="pmid9626557" /> In contrast to the long-chain esters, the half-lives of short-chain estradiol esters such as [[estradiol acetate]] and estradiol hexanoate were the same as that of estradiol.<ref name="pmid9626557" /> As such, whereas short-chain estradiol esters are rapidly [[hydrolysis|hydrolyzed]], long-chain estradiol esters like estradiol stearate are resistant to [[metabolism]].<ref name="pmid9626557" /> Thus, the prolongation of effect of short-chain estradiol esters is purely due to their increased [[lipophilicity]] and slow release from the injected depot, whereas the prolonged duration of long-chain estradiol esters is due both to this property and to their resistance to metabolism.<ref name="pmid9626557" /> Estradiol stearate is susceptible to [[first-pass metabolism]] in the [[liver]], and hence has much greater potency by subcutaneous injection than by [[oral administration]].<ref name="pmid9626557" />

In addition to its [[endogenous]] role, estradiol stearate was previously available as a [[pharmaceutical drug]] for use via [[depot injection|depot]] [[intramuscular injection]].<ref name="Elks2014" /><ref name="IndexNominum2000" /> The medication was introduced between 1938 and 1941 under the brand name Depofollan.<ref name="AntalnéGéza1996" /><ref name="Orvostudomány1960" /> It has been used to treat [[prostate cancer]].<ref name="Medgyaszay1963">{{cite journal | vauthors = Medgyaszay A | title = [Intraocular pressure and hormone therapy] | journal = Ophthalmologica | volume = 145 | issue = 3 | pages = 243–248 | year = 1963 | pmid = 13934365 | doi = 10.1159/000304442 }}</ref><ref name="Sellei1970">{{cite book| vauthors = Sellei C, Eckhardt S, Németh L |title=Chemotherapy of Neoplastic Diseases|url=https://books.google.com/books?id=kcxrAAAAMAAJ|year=1970|publisher= Akadémiai Kiadó | location = Budapest |page=251}}</ref> Estradiol stearate is a long-acting estrogen<ref name="Barth1951" /><ref name="Orvostudomány1960" /> and is said to have been the first long-acting estrogen used in medicine, although it was never widely employed.<ref name="Orvostudomány1960">{{cite book|title=Orvostudomány | trans-title = Medicine | language = Hungarian |url=https://books.google.com/books?id=_EdMAAAAYAAJ|year=1960|publisher=Magyar Tudomanyos Akadémia V. Orvosi Tudományok Osztálya (Hungarian Academy of Sciences V. Department of Medical Sciences) |page=11}}</ref> It was reported to have a [[duration of action|duration]] of more than one month.<ref name="Orvostudomány1960" /> The medication was provided as an [[oil solution]] in [[ampoule]]s containing 15&nbsp;mg estradiol stearate.<ref name="Barth1951">{{cite book|title=Endokrinologie|url=https://books.google.com/books?id=0BExAAAAIAAJ|year=1951|publisher=Johann Ambrosius Barth Verlag.}}</ref><ref name="Sellei1970" /> It was manufactured by Chinoin, a [[Hungary|Hungarian]] [[pharmaceutical company]].<ref name="Barth1951" /><ref name="Sellei1970" /><ref name="AntalnéGéza1996">{{cite book | vauthors = Antalné S, Géza B, István B, Dezső K | title = A Chinoin története (1910–1995) | trans-title = The history of Chinoin | language = Hungarian | url = http://www.gyogyszeresztortenet.hu/wp-content/uploads/2013/08/Egy-mindig-meg%C3%BAjul%C3%B3-v%C3%A1llalat-a-Chinoin-t%C3%B6rt%C3%A9nete.pdf | quote = From the middle of the vitamin D and hannincas years, the research and production of steroid sex hormones was directed by Rezső Weisz. (n) In the latter, the collection of animal raw materials, in addition to chemical operations, required considerable organizational work similar to that of insulin. The intensification of attempts to produce steroid hormones and synthetic steroids, estrogens, over four years may have surpassed even 36 studies of sulfone JDid. Weisz et al., Primarily Kálmán Lányi, developed the most important estrone derivatives of industrial and therapeutic interest, Hogival (estrone acetate), Acrafalin (estradiol propionate) and Depofollan (estradiol stearate), which were marketed in 1938-1940. }}</ref><ref>{{cite book | title = Alkaloida Vegyészeti | trans-title = Alkaloid Chemistry | language = Hungarian | veditors = Gyár R, Tiszavasvári T, Novák K, Hermecz I | date = 2005 | chapter =  Esti beszélgetés – Magyar Gyógyszerkutatók portréi. | publisher = MTA Gyógyszerkémiai és Gyógyszertechnológiai Munkabizottsága (Hungarian Academy of Sciences' Working Committee on Medicinal Chemistry and Pharmaceutical Technology)| trans-chapter = Evening discussion - Portraits of Hungarian Pharmaceutical Researchers. | location = Budapest | url =
http://www.gyogyszeresztortenet.hu/wp-content/uploads/2013/08/Esti-besz%C3%A9lget%C3%A9s.pdf | archive-url = https://web.archive.org/web/20160805140955/http://www.gyogyszeresztortenet.hu/wp-content/uploads/2013/08/Esti-besz%C3%A9lget%C3%A9s.pdf | archive-date=2016-08-05 | quote = Chinoin has achieved good results in the steroid hormones, synthetic steroids, and estrogens since the twenties, protected by 36 patents. The company was one of the first in the world to produce vitamin D, but was also a successful product for Hogival (estrone acetate), Acrofollin (estradiol propionate), Depofollan (estradiol stearate), Acrolutin (progesterone). }}</ref> The compound was studied by Karl Miescher in 1938<ref name="pmid16746750">{{cite journal | vauthors = Miescher K, Scholz C, Tschopp E | title = The activation of female sex hormones: Mono-esters of alpha-oestradiol | journal = The Biochemical Journal | volume = 32 | issue = 8 | pages = 1273–1280 | date = August 1938 | pmid = 16746750 | pmc = 1264184 | doi = 10.1042/bj0321273b }}</ref> and was [[patent]]ed by Miescher and Chinoin in 1939 and 1941, respectively.<ref name="US2156599A">{{Cite patent | country = US | number = 2156599 |url=https://patents.google.com/patent/US2156599A/en|title = Estradiol esters esterified in 3-position and process of making same | inventor = Karl M, Caesar S | gdate = 1939 }}</ref><ref name="US2253669A">{{Cite patent | country = US | number = 2253669 | url=https://patents.google.com/patent/US2253669A/en|title = Estradiol higher fatty acid ester | inventor = Rezso W | assign1 = Current Assignee Chinoin Private Co Ltd | gdate = 1941 }}</ref> A similar clinically used long-acting estradiol ester is [[estradiol undecylate]], which has 11 [[carbon]] [[atom]]s instead of the 18 carbon atoms in estradiol stearate.<ref name="Elks2014" /><ref name="IndexNominum2000" />

{{Affinities and estrogenic potencies of estrogen esters and ethers at the estrogen receptors}}

{{Structural properties of selected estradiol esters}}

== See also ==
* [[List of estrogen esters#Estradiol esters|List of estrogen esters § Estradiol esters]]

== References ==
{{Reflist}}

{{Estradiol}}
{{Estrogens and antiestrogens}}
{{Estrogen receptor modulators}}

[[Category:Abandoned drugs]]
[[Category:Estradiol esters]]
[[Category:Stearate esters]]