Details
Stereochemistry | ABSOLUTE |
Molecular Formula | C27H38O3 |
Molecular Weight | 410.5888 |
Optical Activity | UNSPECIFIED |
Defined Stereocenters | 6 / 6 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
[H][C@@]12CC[C@@](OC(=O)CCCCCC)(C#C)[C@@]1(C)CC[C@]3([H])[C@@]4([H])CCC(=O)C=C4CC[C@@]23[H]
InChI
InChIKey=APTGJECXMIKIET-WOSSHHRXSA-N
InChI=1S/C27H38O3/c1-4-6-7-8-9-25(29)30-27(5-2)17-15-24-23-12-10-19-18-20(28)11-13-21(19)22(23)14-16-26(24,27)3/h2,18,21-24H,4,6-17H2,1,3H3/t21-,22+,23+,24-,26-,27-/m0/s1
DescriptionCurator's Comment: Description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/8520623
https://www.medicines.org.uk/emcmobile/PIL.23891.latest.pdf
http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/018405s023lbl.pdf
Curator's Comment: Description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/8520623
https://www.medicines.org.uk/emcmobile/PIL.23891.latest.pdf
http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/018405s023lbl.pdf
Norethisterone (INN, BAN), also known as Norethindrone (USAN) (brand names Micronor, AYGESTIN, numerous others) is a synthetic progestational hormone (progestin) with actions similar to those of progesterone but functioning as a more potent inhibitor of ovulation. It has weak estrogenic and androgenic properties. The hormone has been used for the treatment of secondary amenorrhea, endometriosis, and abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology, such as submucous fibroids or uterine cancer. AYGESTIN® is not intended, recommended or approved to be used with oncomitant estrogen therapy in postmenopausal women for endometrial protection. Progestins diffuse freely into target cells and bind to the progesterone receptor. Target cells include the female reproductive tract, the mammary gland, the hypothalamus, and the pituitary. Once bound to the receptor, progestins slow the frequency of release of gonadotropin releasing hormone (GnRH) from the hypothalamus and blunt the pre-ovulatory LH surge. Allergic reaction could be: Itching or hives, swelling in your face or hands, swelling or tingling in your mouth or throat, chest tightness, trouble breathing.
CNS Activity
Sources: https://www.ncbi.nlm.nih.gov/pubmed/6319907
Curator's Comment: Known to be CNS penetrant in rat. Human data not available
Norethindrone affects the levels of opioid petides in the rat brain, but it is not clear whether this action is mediated by direct activity within CNS
Originator
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL208 Sources: https://www.ncbi.nlm.nih.gov/pubmed/15189034 |
6.8 nM [Ki] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Preventing | MICRONOR Approved UseIndications Progestin-only oral contraceptives are indicated for the prevention of pregnancy. 2. Efficacy If used perfectly, the first-year failure rate for progestin-only oral contraceptives is 0.5%. However, the typical failure rate is estimated to be closer to 5%, due to late or omitted pills. Table 1 lists the pregnancy rates for users of all major methods of contraception. Table 1: Percentage of Women Experiencing an Unintended Pregnancy During the First Year of Typical Use and the First Year of Perfect Use of Contraception and the Percentage Continuing Use at the End of the First Year. United States. Adapted from Hatcher et al, 1998, Ref. #1 Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%The treatment schedule is one dose within 72 hours after unprotected intercourse, and a second dose 12 hours after the first dose. The Food and Drug Administration has declared the following brands of oral contraceptives to be safe and effective for emergency contraception: Ovral® (1 dose is 2 white pills), Alesse® (1 dose is 5 pink pills), Nordette® or Levlen® (1 dose is 2 light-orange pills), Lo/Ovral® (1 dose is 4 white pills), Triphasil ® or Tri-Levlen® (1 dose is 4 yellow pills) Lactational Amenorrhea Method: LAM is highly effective, temporary method of contraceptionHowever, to maintain effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency or duration of breastfeeds is reduced, bottle feeds are introduced, or the baby reaches six months of age. Source: Trussell J, Contraceptive efficacy. In Hatcher RA, Trussel J, Stewart F, Cates W, Stewart GK, Kowal D, Guest F, Contraceptive Technology: Seventeenth Revised Edition. New York NY: Irvington Publishers, 1998. % of Women Experiencing an Unintended Pregnancy within the First Year of Use % of Women Continuing Use at One Year Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year Method (1) Typical UseAmong typical couples who initiate use of a method (not necessarily for the first time), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason (2) Perfect UseAmong couples who initiate use of a method (not necessarily for the first time) and who use it perfectly (both consistently and correctly), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason (3) (4) ChanceThe percents becoming pregnant in columns (2) and (3) are based on data from populations where contraception is not used and from women who cease using contraception in order to become pregnant. Among such populations, about 89% become pregnant within one year. This estimate was lowered slightly (to 85%) to represent the percent who would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether 85 85 SpermicidesFoams, creams, gels, vaginal suppositories, and vaginal film 26 6 40 Periodic abstinence 25 63 Calendar 9 Ovulation Method 3 Sympto-Thermal Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases 2 Post-Ovulation 1 CapWith spermicidal cream or jelly Parous Women 40 26 42 Nulliparous Women 20 9 56 Sponge Parous Women 40 20 42 Nulliparous Women 20 9 56 Diaphragm 20 6 56 Withdrawal 19 4 CondomWithout spermicides Female (Reality®) 21 5 56 Male 14 3 61 Pill 5 71 Progestin Only 0.5 Combined 0.1 IUD Progesterone T 2.0 1.5 81 Copper T380A 0.8 0.6 78 LNg 20 0.1 0.1 81 Depo-Provera® 0.3 0.3 70 Norplant® and Norplant-2® 0.05 0.05 88 Female Sterilization 0.5 0.5 100 Male Sterilization 0.15 0.10 100 Norethindrone tablets have not been studied for and are not indicated for use in emergency contraception. Launch Date1973 |
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Primary | AYGESTIN Approved UseAYGESTIN® is indicated for the treatment of secondary amenorrhea, endometriosis, and abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology, such as submucous fibroids or uterine cancer. AYGESTIN® is not intended, recommended or approved to be used with concomitant estrogen therapy in postmenopausal women for endometrial protection. Launch Date1982 |
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Primary | AYGESTIN Approved UseAYGESTIN® is indicated for the treatment of secondary amenorrhea, endometriosis, and abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology, such as submucous fibroids or uterine cancer. AYGESTIN® is not intended, recommended or approved to be used with concomitant estrogen therapy in postmenopausal women for endometrial protection. Launch Date1982 |
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Primary | AYGESTIN Approved UseAYGESTIN® is indicated for the treatment of secondary amenorrhea, endometriosis, and abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology, such as submucous fibroids or uterine cancer. AYGESTIN® is not intended, recommended or approved to be used with concomitant estrogen therapy in postmenopausal women for endometrial protection. Launch Date1982 |
Cmax
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
26.19 ng/mL |
5 mg single, oral dose: 5 mg route of administration: Oral experiment type: SINGLE co-administered: |
NORETHINDRONE plasma | Homo sapiens population: HEALTHY age: UNKNOWN sex: FEMALE food status: UNKNOWN |
AUC
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
166.9 ng × h/mL |
5 mg single, oral dose: 5 mg route of administration: Oral experiment type: SINGLE co-administered: |
NORETHINDRONE plasma | Homo sapiens population: HEALTHY age: UNKNOWN sex: FEMALE food status: UNKNOWN |
T1/2
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
8.51 h |
5 mg single, oral dose: 5 mg route of administration: Oral experiment type: SINGLE co-administered: |
NORETHINDRONE plasma | Homo sapiens population: HEALTHY age: UNKNOWN sex: FEMALE food status: UNKNOWN |
Funbound
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
3% |
5 mg single, oral dose: 5 mg route of administration: Oral experiment type: SINGLE co-administered: |
NORETHINDRONE plasma | Homo sapiens population: HEALTHY age: UNKNOWN sex: FEMALE food status: UNKNOWN |
Doses
Dose | Population | Adverse events |
---|---|---|
15 mg 1 times / day multiple, oral Studied dose Dose: 15 mg, 1 times / day Route: oral Route: multiple Dose: 15 mg, 1 times / day Sources: |
unhealthy, 10.2-41.9 years Health Status: unhealthy Condition: Endometriosis Age Group: 10.2-41.9 years Sex: F Sources: |
Other AEs: Weight gain... |
20 uCi single, intravenous Dose: 20 uCi Route: intravenous Route: single Dose: 20 uCi Sources: |
healthy, 25-35 years n = 6 Health Status: healthy Age Group: 25-35 years Sex: F Population Size: 6 Sources: |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
Weight gain | 15 mg 1 times / day multiple, oral Studied dose Dose: 15 mg, 1 times / day Route: oral Route: multiple Dose: 15 mg, 1 times / day Sources: |
unhealthy, 10.2-41.9 years Health Status: unhealthy Condition: Endometriosis Age Group: 10.2-41.9 years Sex: F Sources: |
Overview
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
OverviewOther
Other Inhibitor | Other Substrate | Other Inducer |
---|---|---|
Drug as perpetrator
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Sources: https://pubmed.ncbi.nlm.nih.gov/18356043/ Page: 9.0 |
no | |||
Sources: https://pubmed.ncbi.nlm.nih.gov/18356043/ Page: 9.0 |
no | |||
Sources: https://pubmed.ncbi.nlm.nih.gov/18356043/ Page: 9.0 |
no | |||
Sources: https://pubmed.ncbi.nlm.nih.gov/18356043/ Page: 9.0 |
no | |||
Sources: https://pubmed.ncbi.nlm.nih.gov/18356043/ Page: 9.0 |
no | |||
Sources: https://pubmed.ncbi.nlm.nih.gov/18356043/ Page: 9.0 |
no | |||
Sources: https://pubmed.ncbi.nlm.nih.gov/18356043/ Page: 9.0 |
no | |||
Sources: https://pubmed.ncbi.nlm.nih.gov/18356043/ Page: 9.0 |
no | |||
Sources: https://pubmed.ncbi.nlm.nih.gov/18356043/ Page: 9.0 |
weak [IC50 46 uM] |
Drug as victim
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Sources: https://pubmed.ncbi.nlm.nih.gov/15290871/ Page: 1.0 |
no | |||
Sources: https://pubmed.ncbi.nlm.nih.gov/18356043/ Page: 2.0 |
yes | |||
Sources: https://pubmed.ncbi.nlm.nih.gov/18356043/ Page: 2.0 |
yes | |||
Sources: https://hmdb.ca/metabolites/HMDB0014855 |
yes | |||
Sources: https://hmdb.ca/metabolites/HMDB0014855 |
yes | |||
yes |
Tox targets
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
PubMed
Title | Date | PubMed |
---|---|---|
Induction of estrogen receptor-alpha and -beta activities by synthetic progestins. | 2000 Apr |
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The effect of medroxyprogesterone acetate and norethisterone on the estradiol stimulated proliferation in MCF-7 cells: comparison of continuous combined versus sequential combined estradiol/progestin treatment. | 2001 |
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Biphasic versus monophasic oral contraceptives for contraception. | 2001 |
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Detection of estrogenicity by bioassay on the mouse mammary gland in vivo. | 2001 |
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Counting the costs: comparing depot medroxyprogesterone acetate and norethisterone oenanthate utilisation patterns in South Africa. | 2001 |
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Randomized comparison between orally and transdermally administered hormone replacement therapy regimens of long-term effects on 24-hour ambulatory blood pressure in postmenopausal women. | 2001 Apr |
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Effects of hormone replacement therapy and high-impact physical exercise on skeletal muscle in post-menopausal women: a randomized placebo-controlled study. | 2001 Aug |
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Omental pregnancy in a woman taking the progestogen-only pill. | 2001 Dec |
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Solution structure and dynamics of an open beta-sheet, glycolytic enzyme, monomeric 23.7 kDa phosphoglycerate mutase from Schizosaccharomyces pombe. | 2001 Feb 16 |
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Charcoal treatment and risk of escape ovulation in oral contraceptive users. | 2001 Jan |
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The effects of sequential combined oral 17beta-estradiol norethisterone acetate on insulin sensitivity and body composition in healthy postmenopausal women: a randomized single blind placebo-controlled study. | 2001 Jan-Feb |
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Metabolism of norethisterone and norethisterone derivatives in rat uterus, vagina, and aorta. | 2001 Jul |
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Comparison of a novel norgestimate/ethinyl estradiol oral contraceptive (Ortho Tri-Cyclen Lo) with the oral contraceptive Loestrin Fe 1/20. | 2001 Jun |
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The effects of transdermal estradiol in combination with oral norethisterone on lipoproteins, coagulation, and endothelial markers in postmenopausal women with type 2 diabetes: a randomized, placebo-controlled study. | 2001 Mar |
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Temporary discontinuation: a compliance issue in injectable users. | 2001 Nov |
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Hormone replacement therapy and acquired resistance to activated protein C: results of a randomized, double-blind, placebo-controlled trial. | 2001 Nov |
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Solution structure and backbone dynamics of an engineered arginine-rich subdomain 2 of the hepatitis C virus NS3 RNA helicase. | 2001 Nov 30 |
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A longitudinal study of disturbances of the hypothalamic-pituitary-adrenal axis in women with progestin-negative functional hypothalamic amenorrhea. | 2001 Oct |
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Effect of conjugated estrogens on free IGF-I? | 2001 Sep |
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Influence of postmenopausal hormone replacement therapy on platelet serotonin uptake site and serotonin 2A receptor binding. | 2001 Sep |
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Unscheduled bleeding during initiation of continuous combined hormone replacement therapy: a direct comparison of two combinations of norethindrone acetate and ethinyl estradiol to medroxyprogesterone acetate and conjugated equine estrogens. | 2001 Sep-Oct |
|
An effective hormonal male contraceptive using testosterone undecanoate with oral or injectable norethisterone preparations. | 2002 Feb |
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Effect of rofecoxib on the pharmacokinetics of chronically administered oral contraceptives in healthy female volunteers. | 2002 Feb |
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Hormone replacement therapy can augment vascular relaxation in post-menopausal women with type 2 diabetes. | 2002 Feb |
|
The efficacy of two dosages of a continuous combined hormone replacement regimen. | 2002 Feb 26 |
Sample Use Guides
Secondary amenorrhea, abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology: 2.5 to 10 mg may be given daily for 5 to 10 days to produce secretory transformation of an endometrium that has been adequately primed with either endogenous or exogenous estrogen.
Endometriosis: Initial daily dosage of 5 mg for two weeks. Dosage should be increased by 2.5 mg per day every two weeks until 15 mg per day.
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/1834933
Curator's Comment: Growth of MCF-7 cells was stimulated by norethindrone (10(-8)-10(-5) M), with maximal growth stimulation at 10(-7) M norethindrone after 7 days of treatment
10 - 10000 nM norethindrone stimulates growth of MCF-7 cells
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WHO-ESSENTIAL MEDICINES LIST |
18.3.2
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229295
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223-326-7
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HY3S2K0J0F
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100000085741
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SUB03458MIG
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22846
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31984
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1964
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NORETHINDRONE ENANTHATE
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NORETHINDRONE ENANTHATE
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PRIMARY | Description: A white to creamy white, crystalline powder; odourless. Solubility: Practically insoluble in water; freely soluble in acetone R, methanol R, dehydrated ethanol R, dioxan R and ether R; slightly soluble in light petroleum R. Category: Contraceptive. Storage: Norethisterone enantate should be kept in a tightly closed container, protected from light. Requirements: Norethisterone enantate contains not less than 96.0% and not more than the equivalent of 104.0% of C27H38O3, calculated withreference to the dried substance. | ||
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3836-23-5
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C024319
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ACTIVE MOIETY
SUBSTANCE RECORD