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Revision as of 14:18, 24 November 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Saving copy of the {{drugbox}} taken from revid 456965919 of page Norgestimate for the Chem/Drugbox validation project (updated: 'DrugBank', 'ChEMBL').  Latest revision as of 23:57, 29 September 2024 edit Whywhenwhohow (talk | contribs)Autopatrolled, Extended confirmed users, Pending changes reviewers48,654 edits initial name 
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{{Short description|Chemical compound}}
{{ambox | text = This page contains a copy of the infobox ({{tl|drugbox}}) taken from revid of page ] with values updated to verified values.}}
{{Distinguish|Norgestomet}}
{{Drugbox
{{Use dmy dates|date=October 2021}}
| Verifiedfields = changed
{{cs1 config |name-list-style=vanc |display-authors=6}}
| verifiedrevid = 408343690
{{Infobox drug
| IUPAC_name = (13-ethyl-17-ethynyl-3-hydroxyimino- 1,2,6,7,8,9,10,11,12,14,15,16- dodecahydrocyclopenta phenanthren-17-yl) acetate
| Verifiedfields = verified
| Watchedfields = verified
| verifiedrevid = 462263110
| image = Norgestimate.svg | image = Norgestimate.svg
| width = 250
| alt =
| image2 = Norgestimate molecule ball.png
| width2 = 250
| alt2 =


<!--Clinical data--> <!-- Clinical data -->
| tradename = | pronounce =
| tradename = Ortho Tri-Cyclen, others
| Drugs.com = {{drugs.com|CONS|norgestimate}}
| Drugs.com = {{drugs.com|ppa|ethinyl-estradiol-and-norgestimate}}<br />{{drugs.com|ppa|estradiol-and-norgestimate}}
| MedlinePlus = a601050 | MedlinePlus = a601050
| DailyMedID = Norgestimate
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> | pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_AU_comment =
| pregnancy_US = <!-- A / B / C / D / X -->
| pregnancy_category = | pregnancy_category = Use is contraindicated
| routes_of_administration = ]
| legal_AU = <!-- Unscheduled / S2 / S4 / S8 -->
| class = ]; ]; ]<ref name="pmid16112947" />
| legal_UK = <!-- GSL / P / POM / CD -->
| ATC_prefix = G03
| legal_US = <!-- OTC / Rx-only -->
| legal_status = | ATC_suffix = AA11
| ATC_supplemental = {{ATC|G03|FA13}} (only combinations with ]s)
| routes_of_administration =

<!-- Legal status -->
| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled -->
| legal_AU_comment =
| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->
| legal_BR_comment =
| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_CA_comment =
| legal_DE = <!-- Anlage I, II, III or Unscheduled -->
| legal_DE_comment =
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment =
| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->
| legal_UK_comment =
| legal_US = Rx-only
| legal_US_comment =
| legal_EU =
| legal_EU_comment =
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment =
| legal_status = <!-- For countries not listed above -->


<!--Pharmacokinetic data--> <!-- Pharmacokinetic data -->
| bioavailability = Unknown<ref name="pmid8842581">{{cite journal | vauthors = Fotherby K | title = Bioavailability of orally administered sex steroids used in oral contraception and hormone replacement therapy | journal = Contraception | volume = 54 | issue = 2 | pages = 59–69 | date = August 1996 | pmid = 8842581 | doi = 10.1016/0010-7824(96)00136-9 }}</ref>
| bioavailability =
| protein_bound = • Norelgestromin: 99% (to ])<ref name="pmid16112947" /><br />• Levonorgestrel: 98% (to albumin and {{abbrlink|SHBG|sex hormone-binding globulin}})<ref name="pmid16112947" /><br />• Levonorgestrel acetate: ? (to albumin)<ref name="pmid16112947" />
| protein_bound =
| metabolism = ], ]s (], ], ], ])<ref name="pmid16112947" /><ref name="Prefest FDA Label" /><ref name="Ortho Cyclen FDA Label" />
| metabolism =
| metabolites = • ]<ref name="pmid16112947" /><br />• ]<ref name="pmid16112947" /><br />• ]<ref name="pmid16112947" />
| elimination_half-life = 12-30 hours
| excretion = | onset =
| elimination_half-life = • Norgestimate: very short<ref name="pmid16112947" /><br />• Norelgestromin: 17–37 hours<ref name="Prefest FDA Label" /><ref name="pmid16112947" /><br />• Levonorgestrel: 24–32 hours<ref name="pmid16112947" />
| duration_of_action =
| excretion = ]: 47%<ref name="Ortho Cyclen FDA Label" /><br />]: 37%<ref name="Ortho Cyclen FDA Label" />


<!--Identifiers--> <!-- Identifiers -->
| CASNo_Ref = {{cascite|correct|CAS}} | CAS_number_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 35189-28-7 | CAS_number = 35189-28-7
| ATC_prefix = G03
| ATC_suffix = AA11
| ATC_supplemental =
| PubChem = 6540478 | PubChem = 6540478
| IUPHAR_ligand = 7091
| DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00957 | DrugBank = DB00957
Line 42: Line 73:
| KEGG_Ref = {{keggcite|correct|kegg}} | KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D05209 | KEGG = D05209
| ChEBI_Ref = {{ebicite|changed|EBI}} | ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 50815 | ChEBI = 50815
| ChEMBL_Ref = {{ebicite|changed|EBI}} | ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = <!-- blanked - oldvalue: 1200934 --> | ChEMBL = 1200934
| NIAID_ChemDB =
| C=23 | H=31 | N=1 | O=3
| PDB_ligand =
| molecular_weight = 369.497 g/mol
| synonyms = NGM; ORF-10131; Levonorgestrel acetate oxime; Levonorgestrel 17β-acetate 3-oxime; 17α-Ethynyl-18-methyl-19-nortestosterone 3-oxime 17β-acetate; 17α-Ethynyl-18-methylestr-4-en-17β-ol-3-one 3-oxime 17β-acetate
| smiles = O=C(O2(C#C)CC14(CC12CC)3/C(=C\C(=N\O)CC3)CC4)C

| InChI = 1/C23H31NO3/c1-4-22-12-10-19-18-9-7-17(24-26)14-16(18)6-8-20(19)21(22)11-13-23(22,5-2)27-15(3)25/h2,14,18-21,26H,4,6-13H2,1,3H3/b24-17+/t18-,19+,20+,21-,22-,23-/m0/s1
<!-- Chemical and physical data -->
| InChIKey = KIQQMECNKUGGKA-NMYWJIRABS
| IUPAC_name = phenanthren-17-yl] acetate
| C=23 | H=31 | N=1 | O=3
| SMILES = O=C(O2(C#C)CC14(CC12CC)3/C(=C\C(=N\O)CC3)CC4)C
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C23H31NO3/c1-4-22-12-10-19-18-9-7-17(24-26)14-16(18)6-8-20(19)21(22)11-13-23(22,5-2)27-15(3)25/h2,14,18-21,26H,4,6-13H2,1,3H3/b24-17+/t18-,19+,20+,21-,22-,23-/m0/s1 | StdInChI = 1S/C23H31NO3/c1-4-22-12-10-19-18-9-7-17(24-26)14-16(18)6-8-20(19)21(22)11-13-23(22,5-2)27-15(3)25/h2,14,18-21,26H,4,6-13H2,1,3H3/b24-17+/t18-,19+,20+,21-,22-,23-/m0/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = KIQQMECNKUGGKA-NMYWJIRASA-N | StdInChIKey = KIQQMECNKUGGKA-NMYWJIRASA-N
| density =
| density_notes =
| melting_point = 214
| melting_high = 218
| melting_notes =
| boiling_point =
| boiling_notes =
| solubility =
| sol_units =
| specific_rotation =
}} }}

<!-- Definition and medical uses -->
'''Norgestimate''', sold under the brand name '''Ortho Tri-Cyclen''' among others, is a ] medication which is used in ]s for women and in ].<ref name="pmid16112947">{{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 }}</ref><ref name="Prefest FDA Label">{{cite web | title=Prefest- estradiol/norgestimate kit | website=DailyMed | date=29 February 2016 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=70d00600-b8d3-4820-8db6-40d4536a6f9e | access-date=9 November 2020}}</ref><ref name="Ortho Cyclen FDA Label">{{cite web | title=Ortho Tri Cyclen- norgestimate and ethinyl estradiol kit Ortho Cyclen- norgestimate and ethinyl estradiol kit | website=DailyMed | date=16 May 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=384e7a40-dcbd-4908-bf5e-65abc9932973 | access-date=9 November 2020}}</ref><ref name="LemkeWilliams2008">{{cite book| vauthors = Lemke TL, Williams DA |title=Foye's Principles of Medicinal Chemistry|url=https://books.google.com/books?id=R0W1ErpsQpkC&pg=PA1316|year=2008|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-6879-5|pages=1316–}}</ref> The medication is available in combination with an ] and is not available alone.<ref name="Drugs.com" /> It is taken ].<ref name="pmid16112947" />

<!-- Side effects and mechanism -->
]s of the combination of an estrogen and norgestimate include ], ]s, ], ], ], ] changes, and others.<ref name="Prefest FDA Label" /><ref name="Ortho Cyclen FDA Label" /> Norgestimate is a progestin, or a ] ], and hence is an ] of the ], the ] of progestogens like ].<ref name="pmid16112947" /> It has very weak ]ic activity and no other important ] activity.<ref name="pmid16112947" /> The medication is a ] of ] and to a lesser extent of ] in the body.<ref name="pmid16112947" />

<!-- History, society and culture -->
Norgestimate was patented in 1965 and introduced for medical use, specifically in birth control pills, in 1986.<ref name="RunnebaumRabe2012" /><ref name=Fis2006>{{cite book | vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=479 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA479 |language=en}}</ref> It was introduced for use in menopausal hormone therapy in the United States in 1999.<ref name="FDA2013" /> Norgestimate is sometimes referred to as a "third-generation" progestin.<ref name="Carp2015">{{cite book| vauthors = Carp HJ |title=Progestogens in Obstetrics and Gynecology|url=https://books.google.com/books?id=Ik8SCAAAQBAJ&pg=PA112|date=9 April 2015|publisher=Springer|isbn=978-3-319-14385-9|pages=112}}</ref> It is marketed in birth control pills widely throughout the world, whereas it is available for use in menopausal hormone therapy only in the United States and Brazil.<ref name="Drugs.com" /> Norgestimate is available as a ].<ref name="Drugs.com-Generic">{{Cite web |url= https://www.drugs.com/availability/generic-ortho-tri-cyclen.html |title = Generic Ortho Tri-Cyclen Availability | work = Drugs.com }}</ref> In 2022, the combination with ] was the 99th most commonly prescribed medication in the United States, with more than 6{{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 = Ethinyl Estradiol; Norgestimate Drug Usage Statistics, United States, 2013 - 2022 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/EthinylEstradiolNorgestimate | access-date = 30 August 2024 }}</ref>
{{TOC limit}}

==Medical uses==
Norgestimate is used in ] and in ] for the treatment of ] ]s.<ref name="LemkeWilliams2008" /> It is used in combination with ] in ]s and in combination with ] in menopausal hormone therapy.<ref name="Drugs.com" /><ref name="pmid11499185" />

===Available forms===
Norgestimate is available only in combination with the ]s ] and ].<ref name="Drugs.com" /> These formulations are for use by mouth and are indicated specifically for hormonal contraception and menopausal hormone therapy.<ref name="Drugs.com" /> Norgestimate is not available on its own (i.e., as a standalone medication).<ref name="Drugs.com" />

==Contraindications==
{{See also|Progestin#Contraindications}}

==Side effects==
{{See also|Norelgestromin#Side effects|Progestin#Side effects}}

Norgestimate has mostly been studied in combination with an estrogen, so the ]s of norgestimate specifically or on its own have not been well-defined.<ref name="Prefest FDA Label" /><ref name="Ortho Cyclen FDA Label" />

Side effects associated with the combination of ethinylestradiol and norgestimate in premenopausal women, with greater than or equal to 2% incidence over up to 24 ]s, include ]/] (33%), ] (7.8%), ] (8.4%), ] (6.8%), ] (including ], ], and ]) (6.3%), ]s (including depression and mood alterations) (5.0%), ] (3.2%), ] (2.9%), and ] (2.6%).<ref name="Ortho Cyclen FDA Label" />

Side effects associated with the combination of estradiol and norgestimate in postmenopausal women, with greater than or equal to 5% incidence over one year, include headache (23%), ] (21%), breast pain (16%), ] (12%), ] (12%), ] (11%), ] (9%), ] (9%), ] (8%), ] (8%), ] (7%), ] (7%), ] (6%), ] (6%), ] (6%), ] (6%), flatulence (5%), ] (5%), ] (5%), ] (5%), ] (5%), and ] (5%).<ref name="Prefest FDA Label" />

==Overdose==
{{See also|Progestin#Overdose}}

== Interactions ==

{{See also|Progestin#Interactions}}

==Pharmacology==

===Pharmacodynamics===
], also known as 17β-deacetylnorgestimate, the main ] of norgestimate.]]

Norgestimate is a rapidly and completely converted ], mainly of ] (17β-deacetylnorgestimate or levonorgestrel 3-oxime), but also of ] (3-keto-17β-deacetylnorgestimate) to a lesser extent (22 ± 6% of an administered dose or about 40–70&nbsp;μg)<ref name="pmid8842581" /> and of ] (levonorgestrel 17β-acetate) in very small amounts.<ref name="pmid16112947" /><ref name="LemkeWilliams2008"/><ref name="FalconeHurd2007">{{cite book| vauthors = Falcone T, Hurd WW |title=Clinical Reproductive Medicine and Surgery|url=https://books.google.com/books?id=fOPtaEIKvcIC&pg=PA389|year=2007|publisher=Elsevier Health Sciences|isbn=978-0-323-03309-1|pages=389–}}</ref><ref name="HumansOrganization2007">{{cite book| author1=IARC Working Group on the Evaluation of Carcinogenic Risks to Humans|author2=World Health Organization|author3=International Agency for Research on Cancer|title=Combined Estrogen-progestogen Contraceptives and Combined Estrogen-progestogen Menopausal Therapy|url=https://books.google.com/books?id=aGDU5xibtNgC&pg=PA151|year=2007|publisher=World Health Organization|isbn=978-92-832-1291-1|pages=150–151}}</ref><ref name="pmid12215716">{{cite journal | vauthors = Stanczyk FZ | title = Pharmacokinetics and potency of progestins used for hormone replacement therapy and contraception | journal = Reviews in Endocrine & Metabolic Disorders | volume = 3 | issue = 3 | pages = 211–224 | date = September 2002 | pmid = 12215716 | doi = 10.1023/A:1020072325818 | s2cid = 27018468 }}</ref> Via its ]s, norgestimate has ]ic activity, ] effects, very weak ]ic activity, and no other important ] activity.<ref name="pmid16112947" />

{| class="wikitable mw-collapsible mw-collapsed" style="text-align:left; margin-left:auto; margin-right:auto; border:none;"
|+ class="nowrap" | Relative affinities (%) of norgestimate and metabolites
|-
! Compound || {{abbrlink|PR|Progesterone receptor}} || {{abbrlink|AR|Androgen receptor}} || {{abbrlink|ER|Estrogen receptor}} || {{abbrlink|GR|Glucocorticoid receptor}} || {{abbrlink|MR|Mineralocorticoid receptor}} || {{abbrlink|SHBG|Sex hormone-binding globulin}} || {{abbrlink|CBG|Corticosteroid binding globulin}}
|-
| Norgestimate || 15 || 0 || 0 || 1 || 0 || 0 || 0
|-
| ] ({{abbr|17β-deAc-NGM|17β-deacetylnorgestimate}}) || 10 || 0 || ? || ? || ? || 0 || ?
|-
| ] ({{abbr|3-keto-17β-deAc-NGM|3-keto-17β-deacetylnorgestimate}}) || 150–162 || 45 || 0 || 1–8 || 17–75 || 50 || 0
|-
| ] ({{abbr|3-keto-NGM|3-ketonorgestimate}}) || 135 || ? || 0 || ? || ? || 0 || ?
|- class="sortbottom"
| colspan="8" style="width: 1px; background-color:#eaecf0; text-align: center;" | '''Notes:''' Values are percentages (%). Reference ]s (100%) were ] for the {{abbrlink|PR|progesterone receptor}}, ] for the {{abbrlink|AR|androgen receptor}}, ] for the {{abbrlink|ER|estrogen receptor}}, {{abbrlink|DEXA|dexamethasone}} for the {{abbrlink|GR|glucocorticoid receptor}}, ] for the {{abbrlink|MR|mineralocorticoid receptor}}, {{abbrlink|DHT|dihydrotestosterone}} for {{abbrlink|SHBG|sex hormone-binding globulin}}, and ] for {{abbrlink|CBG|Corticosteroid-binding globulin}}. '''Sources:''' <ref name="pmid2170822">{{cite journal | vauthors = Kuhl H | title = Pharmacokinetics of oestrogens and progestogens | journal = Maturitas | volume = 12 | issue = 3 | pages = 171–197 | date = September 1990 | pmid = 2170822 | doi = 10.1016/0378-5122(90)90003-o }}</ref><ref name="pmid16112947" /><ref name="pmid10599548">{{cite journal | vauthors = Philibert D, Bouchoux F, Degryse M, Lecaque D, Petit F, Gaillard M | title = The pharmacological profile of a novel norpregnance progestin (trimegestone) | journal = Gynecological Endocrinology | volume = 13 | issue = 5 | pages = 316–326 | date = October 1999 | pmid = 10599548 | doi = 10.3109/09513599909167574 }}</ref>
|}

====Progestogenic activity====
Norgestimate is a ], or an ] of the ].<ref name="pmid16112947" /> The ] of norgestimate and its active metabolites for the progesterone receptor compared to ] (100%) are 15% for norgestimate, 10% for norelgestromin, 150% for levonorgestrel, and 135% for levonorgestrel acetate.<ref name="pmid16112947" /> Because of their low concentrations, norgestimate and levonorgestrel acetate are not thought to contribute significantly to the ] of norgestimate.<ref name="pmid16112947" /> In addition, although levonorgestrel binds to the progesterone receptor with much higher ] than norelgestromin, levonorgestrel has high affinity for ] (SHBG) (87% of that of testosterone), which may limit its activity, whereas norelgestromin does not bind to SHBG.<ref name="pmid16112947" /><ref name="Ortho Cyclen FDA Label" /><ref name="pmid1415445" /> The ]-inhibiting dosage of norgestimate is 200&nbsp;μg/day.<ref name="pmid16112947" />

====Androgenic activity====
In addition to its progestogenic activity, norgestimate has weak ]ic activity.<ref name="pmid16112947" /> However, the medication shows less androgenic activity than related ] progestins like levonorgestrel and ].<ref name="LemkeWilliams2008" /><ref name="pmid2571595">{{cite journal | vauthors = Chapdelaine A, Desmarais JL, Derman RJ | title = Clinical evidence of the minimal androgenic activity of norgestimate | journal = International Journal of Fertility | volume = 34 | issue = 5 | pages = 347–352 | year = 1989 | pmid = 2571595 }}</ref> Norgestimate and norelgestromin have negligible affinity for the ] (both 0% of the affinity of ]), while levonorgestrel has considerable affinity for the androgen receptor (45% of that of metribolone).<ref name="pmid16112947" /> In addition to their lack of affinity for the androgen receptor, norgestimate and norelgestromin have virtually no affinity for SHBG, and therefore do not displace ] from this carrier protein (although levonorgestrel does still bind with high affinity to SHBG and hence could increase free testosterone levels via occupation of SHBG).<ref name="LemkeWilliams2008" /><ref name="pmid16112947" /> In accordance, ]s of norgestimate have observed minimal androgenic ]s in women treated with the medication.<ref name="pmid2571595" /> As an example, clinical studies have found that norgestimate does not appreciably inhibit the increase in SHBG levels produced by ].<ref name="pmid1415445" /> This is of interest because ]s increase and ]s decrease ] of SHBG and by extension circulating levels of SHBG.<ref name="pmid1415445" />

The relative binding affinity of norgestimate and its metabolite norelgestromin for the rat ] ] (AR) are 0.3% and 1.3% of those of ] (DHT), respectively, whereas the respective values for ] and ] are 22% and 15%.<ref name="pmid1415445">{{cite journal | vauthors = Phillips A, Hahn DW, McGuire JL | title = Preclinical evaluation of norgestimate, a progestin with minimal androgenic activity | journal = American Journal of Obstetrics and Gynecology | volume = 167 | issue = 4 Pt 2 | pages = 1191–1196 | date = October 1992 | pmid = 1415445 | doi = 10.1016/s0002-9378(12)90410-x }}</ref> Based on these findings, the ratios of AR to PR binding are 219 for norgestimate and 48 for norelgestromin, whereas the ratios for ], levonorgestrel, and gestodene are 93, 11, and 28, respectively.<ref name="pmid1415445" /> As such, norgestimate and norelgestromin would appear to have much lower androgenic potency than other 19-nortestosterone progestins.<ref name="pmid1415445" /> However, levonorgestrel is an important metabolite of both norgestimate and norelgestromin, and it may serve to increase their androgenic potency to some degree.<ref name="pmid16112947" /><ref name="pmid1415445" />

When norgestimate is combined with ethinylestradiol, which is potently ]ic, there are only antiandrogenic effects overall and the combination is suitable for treatment of ].<ref name="pmid11499185" />

====Other activities====
Norgestimate and its active metabolites do not bind to other ]s besides the progesterone and androgen receptors and hence have no other ] hormonal activity.<ref name="pmid16112947" /> This includes ]ic, ], ], and ] activity.<ref name="pmid16112947" /> However, levonorgestrel has been found to ] ] and ] ] ]s '']'' to some extent.<ref name="pmid16112947" />

===Pharmacokinetics===
Norgestimate is rapidly and almost completely ] into its ]s, mainly ] (the primary active metabolite) and to a lesser extent ], upon ] ingestion.<ref name="pmid16112947" /><ref name="Prefest FDA Label" /><ref name="Ortho Cyclen FDA Label" /> As a result, only very low concentrations (70&nbsp;pg/mL) of norgestimate itself are detectable in the circulation, and only for about 6&nbsp;hours after an oral dose.<ref name="pmid16112947" /><ref name="Mishell1999">{{cite book| vauthors = Mishell DR |title=Progestins and Antiprogestins in Clinical Practice|url=https://books.google.com/books?id=vGJJHsJASekC|date=10 November 1999|publisher=Taylor & Francis|isbn=978-0-8247-8291-7|pages=133–151}}</ref> The oral ] of norgestimate is unknown.<ref name="Mishell1999" /><ref name="pmid8842581" /> This is due to the rapid and extensive metabolism of norgestimate, which makes determination of overall bioavailability difficult and necessitates methods other than ] (AUC) to do so.<ref name="Mishell1999" /> ] of norelgestromin (3,500&nbsp;pg/mL) are reached at approximately 2&nbsp;hours following administration of norgestimate.<ref name="Prefest FDA Label" /><ref name="Ortho Cyclen FDA Label" /><ref name="pmid11499185">{{cite journal | vauthors = Henzl MR | title = Norgestimate. From the laboratory to three clinical indications | journal = The Journal of Reproductive Medicine | volume = 46 | issue = 7 | pages = 647–661 | date = July 2001 | pmid = 11499185 }}</ref> Co-administration of norgestimate with a high-fat meal has been found to significantly decrease peak levels of norelgestromin, although the ] levels of norelgestromin are not significantly altered by food.<ref name="Prefest FDA Label" /> ] levels of norelgestromin and levonorgestrel are reached within 21&nbsp;days of treatment with norgestimate.<ref name="Ortho Cyclen FDA Label" /> There is an approximate 2-fold accumulation in levels of norelgestromin and a non-linear approximate 8-fold accumulation in levels of levonorgestrel with continuous administration of norgestimate.<ref name="Ortho Cyclen FDA Label" /> The accumulation of levonorgestrel is thought to be a result of its high ] for SHBG, which limits its ].<ref name="Ortho Cyclen FDA Label" /> The ] of norelgestromin is approximately 99% and it is bound to ] but not to SHBG.<ref name="Prefest FDA Label" /><ref name="Ortho Cyclen FDA Label" /><ref name="pmid16112947" /> Conversely, levonorgestrel is approximately 98% bound to ]s and is bound to both albumin and SHBG.<ref name="pmid16112947" /><ref name="Ortho Cyclen FDA Label" />

Norgestimate is extensively metabolized into its active metabolites during ] in the ] and ]s.<ref name="pmid16112947" /><ref name="Prefest FDA Label" /><ref name="Ortho Cyclen FDA Label" /> The major metabolite of norgestimate is norelgestromin and is formed from norgestimate via ] in the liver and intestines.<ref name="Prefest FDA Label" /> A more minor metabolite of norgestimate is levonorgestrel, which accounts for 20 to 25% (22 ± 6%) of an administered dose or about 40 to 70&nbsp;μg norgestimate,<ref name="Mishell1999" /><ref name="pmid8842581" /> and a very minor metabolite of norgestimate is ].<ref name="Prefest FDA Label" /> Both of these ]s are ] similarly to norgelstromin.<ref name="pmid16112947" /><ref name="Prefest FDA Label" /> With a typical oral contraceptive dosage of norgestimate of 200 to 250&nbsp;μg/day, an amount of 50 to 60&nbsp;μg/day levonorgestrel may be produced.<ref name="Mishell1999" /> This is similar to the ]-inhibiting dosage of levonorgestrel, and suggests that norgestimate may act in considerable part as a prodrug specifically of levonorgestrel.<ref name="Mishell1999" /><ref name="pmid16112947" /> Following their formation, the ]s of norgestimate are inactivated via ], ], and ] into levonorgestrel metabolites.<ref name="pmid16112947" /><ref name="Ortho Cyclen FDA Label" /> The ] of norelgestromin is between 17 and 37&nbsp;hours and of levonorgestrel is between 24 and 32&nbsp;hours.<ref name="Prefest FDA Label" /><ref name="pmid16112947" /> The metabolites of norgestimate are ] 47% in ] and 37% in ].<ref name="Prefest FDA Label" /><ref name="Ortho Cyclen FDA Label" /> Unchanged norgestimate is undetectable in urine.<ref name="Ortho Cyclen FDA Label" />

==Chemistry==
{{See also|List of progestogens|Progestogen ester|List of progestogen esters}}

Norgestimate, also known as 17α-ethynyl-18-methyl-19-nortestosterone 3-oxime 17β-acetate or as 17α-ethynyl-18-methylestr-4-en-17β-ol-3-one 3-oxime 17β-acetate, is a ] ] ] and a ] of ].<ref name="Elks2014" /><ref name="Drugs.com" /> It is a ] of ]s.<ref name="US7345183">{{Cite patent | country = US | number = 7345183 |url=https://www.google.com/patents/US7345183|title = Process for obtaining norelgestromin in different relations of isomers e and Z | assign1 = Gador SA | inventor = Tombari DG, Vecchioli A | gdate = 18 March 2008 }}</ref> Norgestimate is more specifically a derivative of ] (17α-ethynyl-19-nortestosterone) and is a member of the ] (18-methylestrane) subgroup of the ] family of progestins.<ref name="StraussBarbieri2009">{{cite book| vauthors = Schreiber CA, Barnhart K | chapter = Chapter 36 - Contraception | veditors = Strauss JF, Barbieri RL |title=Yen and Jaffe's Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management| chapter-url = https://books.google.com/books?id=NudwnhxY8kYC&pg=PA878|year=2009|publisher=Elsevier Health Sciences|isbn=978-1-4160-4907-4|pages=878–}}</ref> It is the C3 ] and C17β ] ] of ] and is also known as levonorgestrel acetate oxime.<ref name="Skouby1997">{{cite book| vauthors = Skouby SO |title=Clinical Perspectives on a New Gestodene Oral Contraceptive Containing 20&nbsp;μg of Ethinylestradiol|url=https://books.google.com/books?id=IYj54F5zvM4C&pg=PA11|date=15 July 1997|publisher=CRC Press|isbn=978-1-85070-786-8|pages=11–}}</ref> A related compound is ] (norethisterone-3-oxime 17β-acetate).<ref name="Elks2014" />

==History==
Norgestimate was introduced as a component of combined oral contraceptives in 1986.<ref name="RunnebaumRabe2012">{{cite book | vauthors = van Keep PA, Rekers H | chapter = Trends in Contraception and Contraceptive Research | veditors = Runnebaum BC, Rabe T, Kiesel L |title=Female Contraception: Update and Trends |chapter-url=https://books.google.com/books?id=LtT6CAAAQBAJ&pg=PA13 |date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-73790-9|pages=13–}}</ref> Based on its year of introduction, norgestimate is sometimes described as a "third-generation" progestin.<ref name="Carp2015" /> Norgestimate was approved in combination with estradiol for use in menopausal hormone therapy in 1999 in the United States, and a generic version of this preparation became available in this country in 2005.<ref name="FDA2013">{{cite book|author=Food and Drug Administration|title=Approved Drug Products with Therapeutic Equivalence Evaluations - FDA Orange Book 33rd Edition (2013): FDA Orange Book 33rd Edition (2013)|date=15 August 2023 |url=https://books.google.com/books?id=5uSMDAAAQBAJ&pg=PR190|publisher=Logos Press|isbn=978-1-934899-83-0|pages=190–}}</ref>

==Society and culture==

===Generic names===
Norgestimate is the ] of the drug and its {{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|USAN|United States Adopted Name}}, {{abbrlink|USP|United States Pharmacopeia}}, {{abbrlink|BAN|British Approved Name}}, and {{abbrlink|DCF|Dénomination Commune Française}}.<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=PA887|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=887–}}</ref><ref name="Drugs.com">{{Cite web|url=https://www.drugs.com/international/norgestimate.html|title = Norgestimate and Ethinyl Estradiol - FDA prescribing information, side effects and uses}}</ref> It is also known by its developmental code name ORF-10131.<ref name="Elks2014" /><ref name="Drugs.com" />

===Brand names===
Norgestimate is marketed in combination with ] as a birth control pill under the brand names Amicette, Cilest, Cyclen, Edelsin, Effiprev, Estarylla, MonoNessa, Orlon, Ortho Tri-Cyclen, Ortho Tri-Cyclen Lo, Ortho-Cyclen, Pramino, Previfem, Sprintec, Triafemi, TriCilest, Tri-Cyclen, Tri-Cyclen LO, Tridette, Tri-Estarylla, Tri-Linyah, TriNessa, Tri-Previfem, and Tri-Sprintec.<ref name="Elks2014" /><ref name="Drugs.com" /> It is marketed in combination with ] for menopausal hormone therapy under the brand name Prefest.<ref name="Drugs.com" />

===Availability===
Norgestimate in combination with ] is marketed widely throughout the world, including in the United States, Canada, the United Kingdom, Ireland, elsewhere throughout Europe, South Africa, Latin America, and Asia.<ref name="Drugs.com" /> Unlike the combined birth control pills of norgestimate with ethinylestradiol, the combination of norgestimate with ], sold under the brand name Prefest for menopausal hormone therapy, is reportedly only marketed in the United States and Brazil.<ref name="Drugs.com" />

==Research==
A 2017 study found that norgestimate inhibits ] ] formation and resensitizes ]-resistant '']'' to ]s.<ref name="pmid28758016">{{cite journal | vauthors = Yoshii Y, Okuda KI, Yamada S, Nagakura M, Sugimoto S, Nagano T, Okabe T, Kojima H, Iwamoto T, Kuwano K, Mizunoe Y | display-authors = 6 | title = Norgestimate inhibits staphylococcal biofilm formation and resensitizes methicillin-resistant ''Staphylococcus aureus'' to β-lactam antibiotics | journal = npj Biofilms and Microbiomes | volume = 3 | pages = 18 | date = 2017 | pmid = 28758016 | pmc = 5522392 | doi = 10.1038/s41522-017-0026-1 }}</ref> In contrast, ] showed much weaker activity, indicating that the ] of norgestimate is important for the activity.<ref name="pmid28758016" /> It was suggested by the researchers that norgestimate may be a promising ] for the development of new antibiotics.<ref name="pmid28758016" />

== References ==
{{Reflist}}

== Further reading ==
{{refbegin}}
* {{cite journal | vauthors = Henzl MR | title = Norgestimate. From the laboratory to three clinical indications | journal = The Journal of Reproductive Medicine | volume = 46 | issue = 7 | pages = 647–661 | date = July 2001 | pmid = 11499185 }}
* {{cite journal | vauthors = Curran MP, Wagstaff AJ | title = Estradiol and norgestimate: a review of their combined use as hormone replacement therapy in postmenopausal women | journal = Drugs & Aging | volume = 18 | issue = 11 | pages = 863–885 | date = 2001 | pmid = 11772126 | doi = 10.2165/00002512-200118110-00007 | s2cid = 22720686 }}
* {{cite journal | vauthors = Curran MP, Wagstaff AJ | title = Spotlight on estradiol and norgestimate as hormone replacement therapy in postmenopausal women | journal = Treatments in Endocrinology | volume = 1 | issue = 2 | pages = 127–129 | date = 2002 | pmid = 15765628 | doi = 10.2165/00024677-200201020-00006 | s2cid = 1936039 }}
{{refend}}

{{Progestogens and antiprogestogens}}
{{Androgens and antiandrogens}}
{{Progesterone receptor modulators}}
{{Androgen receptor modulators}}
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