Peringatan Keamanan

The oral LD50 in mice 6 g/kg and the TDLo in human women is 42 mg/kg.L10433 There have been no reports of serious ill effects following overdose of oral contraceptives, including following ingestion by children.L10307,L10313 Symptoms of overdosage are likely to be consistent with the adverse effect profile of the contraceptive and may, therefore, include significant nausea and/or vomiting.

Norethisterone

DB00717

small molecule approved

Deskripsi

Norethisterone, also known as norethindrone, is a synthetic progestational hormone belonging to the 19-nortestosterone-derived class of progestins.A10367 It is further classified as a second-generation progestin, along with levonorgestrel and its derivatives, and is the active form of several other progestins including norethynodrel and lynestrenol.A10367 Norethisterone mimics the actions of endogenous progesterone, albeit with a greater potency,A188075 and is used on its own or in combination with estrogen derivatives in a variety of applications including contraception and hormone replacement therapy.L9527,L10301,L10304,L10307 First derived in 1951 in Mexico City, norethisterone was originally intended for use as a remedy for irregular menstruation and endometriosis, and was not marketed for use as an oral contraceptive until 1962.L10439

Struktur Molekul 2D

Berat 298.4192
Wujud solid

Peta Jejaring Molekuler
Legenda: Obat • Target • Gen • Enzim • (Panah → menunjukkan arah efek / relasi) • Transporter • Carrier

Profil Farmakokinetik

Waktu Paruh (Half-Life) The half-life of norethisterone has been variably estimated as 8-10 hours.[A188072,A188069,A10367,L9527,L10313]
Volume Distribusi The volume of distribution of norethisterone is approximately 4 L/kg.[A188072,L10307] Sulfated metabolites of norethisterone, as well as small quantities of parent drug, have been shown to distribute into breast milk.[A188153]
Klirens (Clearance) The plasma clearance of norethisterone has been estimated as 0.4 L/hr/kg,[A188072,L10307] and the intrinsic clearance is approximately 73-81 L/h.[A188147]

Absorpsi

The Cmax of norethisterone following oral administration of a single dose ranges from 5.39 to 7.36 ng/mL with a Tmax of 1-2 hours.L9527,L10304,L10307 AUC0-24 values following single oral doses range from approximately 30 to 37 ng*hr/mL.L9527,L10304,L10307 The oral bioavailability of norethisterone is approximately 64%.L10307 When applied transdermally, norethisterone is well-absorbed through the skin, reaches steady-state concentrations within 24 hours, and has a Cmax ranging from 617 to 1060 pg/mL at steady state.L10301 Norethisterone is often formulated as norethisterone acetate, which is completely and rapidly deacetylated to norethisterone following oral administration - the disposition of norethisterone acetate is indistinguishable from that of orally administered norethisterone.L10307

Metabolisme

Norethisterone is extensively metabolized, primarily in the liver, to a number of metabolites via partial and total reduction of its A-ring.A188078 The enzymes predominantly involved are 3?- and 3?-hydroxysteroid dehydrogenase (HSD) as well as 5?- and 5?-reductase.A188078,A188075 The 5?-reduced metabolites, including 5?-dihydronorethisterone and its derivatives, appear to carry biological activity while the 5?-reduced metabolites appear inactive.A188075 Norethisterone and its metabolites are also extensively conjugated - most of the plasmatic metabolites are sulfate conjugates, while most of the urinary metabolites are glucuronide conjugates.A188072,L10307 The major metabolites in plasma are a disulfate conjugate of 3?,5?-tetrahydronorethisterone and a monosulfate conjugate of 3?,5?-tetrahydronorethisterone, while the major metabolite(s) in the urine are comprised of glucuronide and/or sulfate conjugates of 3?,5?-tetrahydronorethisterone.A188150 Norethisterone has also been observed to undergo some degree of metabolism via the cytochrome P450 enzyme system, predominantly by CYP3A4 and, to a much lesser extent, by CYP2C19, CYP1A2, and CYP2A6.A35871 The metabolites generated by these reactions have not been fully characterized.

Rute Eliminasi

Following administration of radio-labeled norethisterone, slightly more than 50% of the administered dose was eliminated in the urine and 20-40% was eliminated in the feces.A182033

Interaksi Makanan

1 Data
  • 1. Take with or without food. Co-administration with food slightly alters pharmacokinetics, but not to a clinically significant extent.

Interaksi Obat

914 Data
Phenytoin The metabolism of Norethisterone can be increased when combined with Phenytoin.
Fosphenytoin The metabolism of Norethisterone can be increased when combined with Fosphenytoin.
Acitretin The therapeutic efficacy of Norethisterone can be decreased when used in combination with Acitretin.
Atazanavir The serum concentration of Norethisterone can be increased when it is combined with Atazanavir.
Boceprevir The serum concentration of Norethisterone can be increased when it is combined with Boceprevir.
Prucalopride The serum concentration of Norethisterone can be decreased when it is combined with Prucalopride.
Sugammadex The serum concentration of Norethisterone can be decreased when it is combined with Sugammadex.
Thalidomide Norethisterone may increase the thrombogenic activities of Thalidomide.
Ulipristal The therapeutic efficacy of Norethisterone can be decreased when used in combination with Ulipristal.
Colesevelam The serum concentration of Norethisterone can be decreased when it is combined with Colesevelam.
Darunavir The serum concentration of Norethisterone can be decreased when it is combined with Darunavir.
Ursodeoxycholic acid The therapeutic efficacy of Ursodeoxycholic acid can be decreased when used in combination with Norethisterone.
Glycochenodeoxycholic Acid The therapeutic efficacy of Glycochenodeoxycholic Acid can be decreased when used in combination with Norethisterone.
Cholic Acid The therapeutic efficacy of Cholic Acid can be decreased when used in combination with Norethisterone.
Glycocholic acid The therapeutic efficacy of Glycocholic acid can be decreased when used in combination with Norethisterone.
Deoxycholic acid The therapeutic efficacy of Deoxycholic acid can be decreased when used in combination with Norethisterone.
Taurocholic acid The therapeutic efficacy of Taurocholic acid can be decreased when used in combination with Norethisterone.
Obeticholic acid The therapeutic efficacy of Obeticholic acid can be decreased when used in combination with Norethisterone.
Tauroursodeoxycholic acid The therapeutic efficacy of Tauroursodeoxycholic acid can be decreased when used in combination with Norethisterone.
Bamet-UD2 The therapeutic efficacy of Bamet-UD2 can be decreased when used in combination with Norethisterone.
cis-Diamminechlorocholylglycinateplatinum(II) The therapeutic efficacy of cis-Diamminechlorocholylglycinateplatinum(II) can be decreased when used in combination with Norethisterone.
Dehydrocholic acid The therapeutic efficacy of Dehydrocholic acid can be decreased when used in combination with Norethisterone.
Hyodeoxycholic Acid The therapeutic efficacy of Hyodeoxycholic Acid can be decreased when used in combination with Norethisterone.
Aramchol The therapeutic efficacy of Aramchol can be decreased when used in combination with Norethisterone.
Ox bile extract The therapeutic efficacy of Ox bile extract can be decreased when used in combination with Norethisterone.
Chenodeoxycholic acid The therapeutic efficacy of Chenodeoxycholic acid can be decreased when used in combination with Norethisterone.
Taurochenodeoxycholic acid The therapeutic efficacy of Taurochenodeoxycholic acid can be decreased when used in combination with Norethisterone.
Tranexamic acid Norethisterone may increase the thrombogenic activities of Tranexamic acid.
Clobazam The serum concentration of Norethisterone can be decreased when it is combined with Clobazam.
Colestipol Colestipol can cause a decrease in the absorption of Norethisterone resulting in a reduced serum concentration and potentially a decrease in efficacy.
Sevelamer Sevelamer can cause a decrease in the absorption of Norethisterone resulting in a reduced serum concentration and potentially a decrease in efficacy.
Cholestyramine Cholestyramine can cause a decrease in the absorption of Norethisterone resulting in a reduced serum concentration and potentially a decrease in efficacy.
Griseofulvin The metabolism of Norethisterone can be increased when combined with Griseofulvin.
Tixocortol The serum concentration of Tixocortol can be increased when it is combined with Norethisterone.
Fluocortin The serum concentration of Fluocortin can be increased when it is combined with Norethisterone.
Fluperolone The serum concentration of Fluperolone can be increased when it is combined with Norethisterone.
Fluclorolone The serum concentration of Fluclorolone can be increased when it is combined with Norethisterone.
Dexamethasone The serum concentration of Dexamethasone can be increased when it is combined with Norethisterone.
Flunisolide The serum concentration of Flunisolide can be increased when it is combined with Norethisterone.
Beclomethasone dipropionate The serum concentration of Beclomethasone dipropionate can be increased when it is combined with Norethisterone.
Fluocinolone acetonide The serum concentration of Fluocinolone acetonide can be increased when it is combined with Norethisterone.
Triamcinolone The serum concentration of Triamcinolone can be increased when it is combined with Norethisterone.
Corticotropin The serum concentration of Corticotropin can be increased when it is combined with Norethisterone.
Cortisone acetate The serum concentration of Cortisone acetate can be increased when it is combined with Norethisterone.
Fluprednidene The serum concentration of Fluprednidene can be increased when it is combined with Norethisterone.
Meprednisone The serum concentration of Meprednisone can be increased when it is combined with Norethisterone.
Dexamethasone isonicotinate The serum concentration of Dexamethasone isonicotinate can be increased when it is combined with Norethisterone.
Deflazacort The serum concentration of Deflazacort can be increased when it is combined with Norethisterone.
Cortivazol The serum concentration of Cortivazol can be increased when it is combined with Norethisterone.
Prednylidene The serum concentration of Prednylidene can be increased when it is combined with Norethisterone.
Cloprednol The serum concentration of Cloprednol can be increased when it is combined with Norethisterone.
Mometasone furoate The serum concentration of Mometasone furoate can be increased when it is combined with Norethisterone.
Hydrocortisone acetate The serum concentration of Hydrocortisone acetate can be increased when it is combined with Norethisterone.
Hydrocortisone succinate The serum concentration of Hydrocortisone succinate can be increased when it is combined with Norethisterone.
Prednisolone phosphate The serum concentration of Prednisolone phosphate can be increased when it is combined with Norethisterone.
Prednisolone hemisuccinate The serum concentration of Prednisolone hemisuccinate can be increased when it is combined with Norethisterone.
Methylprednisolone hemisuccinate The serum concentration of Methylprednisolone hemisuccinate can be increased when it is combined with Norethisterone.
Prednisone acetate The serum concentration of Prednisone acetate can be increased when it is combined with Norethisterone.
Clocortolone acetate The serum concentration of Clocortolone acetate can be increased when it is combined with Norethisterone.
Melengestrol acetate The serum concentration of Melengestrol acetate can be increased when it is combined with Norethisterone.
Betamethasone phosphate The serum concentration of Betamethasone phosphate can be increased when it is combined with Norethisterone.
Cortisone The serum concentration of Cortisone can be increased when it is combined with Norethisterone.
Betamethasone The serum concentration of Betamethasone can be increased when it is combined with Norethisterone.
Prednisone The serum concentration of Prednisone can be increased when it is combined with Norethisterone.
Hydrocortisone The serum concentration of Hydrocortisone can be increased when it is combined with Norethisterone.
Prednisolone The serum concentration of Prednisolone can be increased when it is combined with Norethisterone.
Methylprednisolone The serum concentration of Methylprednisolone can be increased when it is combined with Norethisterone.
Paramethasone The serum concentration of Paramethasone can be increased when it is combined with Norethisterone.
Fluticasone furoate The serum concentration of Fluticasone furoate can be increased when it is combined with Norethisterone.
Fluticasone The serum concentration of Fluticasone can be increased when it is combined with Norethisterone.
Fluticasone propionate The serum concentration of Fluticasone propionate can be increased when it is combined with Norethisterone.
Budesonide The serum concentration of Budesonide can be increased when it is combined with Norethisterone.
Hydrocortisone cypionate The serum concentration of Hydrocortisone cypionate can be increased when it is combined with Norethisterone.
Fludrocortisone The serum concentration of Fludrocortisone can be increased when it is combined with Norethisterone.
Trilostane The serum concentration of Trilostane can be increased when it is combined with Norethisterone.
Ciclesonide The serum concentration of Ciclesonide can be increased when it is combined with Norethisterone.
Aldosterone The serum concentration of Aldosterone can be increased when it is combined with Norethisterone.
Fluprednisolone The serum concentration of Fluprednisolone can be increased when it is combined with Norethisterone.
Melengestrol The serum concentration of Melengestrol can be increased when it is combined with Norethisterone.
Clobetasol propionate The serum concentration of Clobetasol propionate can be increased when it is combined with Norethisterone.
Fluocinonide The serum concentration of Fluocinonide can be increased when it is combined with Norethisterone.
Hydrocortisone butyrate The serum concentration of Hydrocortisone butyrate can be increased when it is combined with Norethisterone.
Desoximetasone The serum concentration of Desoximetasone can be increased when it is combined with Norethisterone.
Mometasone The serum concentration of Mometasone can be increased when it is combined with Norethisterone.
Fluocortolone The serum concentration of Fluocortolone can be increased when it is combined with Norethisterone.
Prednisolone acetate The serum concentration of Prednisolone acetate can be increased when it is combined with Norethisterone.
Fluorometholone The serum concentration of Fluorometholone can be increased when it is combined with Norethisterone.
Difluocortolone The serum concentration of Difluocortolone can be increased when it is combined with Norethisterone.
Flumethasone The serum concentration of Flumethasone can be increased when it is combined with Norethisterone.
Methylprednisolone aceponate The serum concentration of Methylprednisolone aceponate can be increased when it is combined with Norethisterone.
Vitamin A The therapeutic efficacy of Norethisterone can be decreased when used in combination with Vitamin A.
Bexarotene The therapeutic efficacy of Norethisterone can be decreased when used in combination with Bexarotene.
Alitretinoin The therapeutic efficacy of Norethisterone can be decreased when used in combination with Alitretinoin.
Tretinoin The therapeutic efficacy of Norethisterone can be decreased when used in combination with Tretinoin.
Tazarotene The therapeutic efficacy of Norethisterone can be decreased when used in combination with Tazarotene.
Etretinate The therapeutic efficacy of Norethisterone can be decreased when used in combination with Etretinate.
Isotretinoin The therapeutic efficacy of Norethisterone can be decreased when used in combination with Isotretinoin.
4-Oxoretinol The therapeutic efficacy of Norethisterone can be decreased when used in combination with 4-Oxoretinol.
Fenretinide The therapeutic efficacy of Norethisterone can be decreased when used in combination with Fenretinide.
Ro 12-7310 The therapeutic efficacy of Norethisterone can be decreased when used in combination with Ro 12-7310.

Target Protein

Progesterone receptor PGR
Androgen receptor AR
Glucocorticoid receptor NR3C1

Referensi & Sumber

Synthesis reference: Djerassi C, Miramontes L, Rosenkranz G, Sondheimer F: Steroids LIV. Synthesis of 19-nor-17?-ethynyltestosterone and 19-nor-17?-methyltestosterone. Am J Obstet Gynecol. 2006. 194(1):289.
Artikel (PubMed)
  • PMID: 2143719
    Stanczyk FZ, Roy S: Metabolism of levonorgestrel, norethindrone, and structurally related contraceptive steroids. Contraception. 1990 Jul;42(1):67-96.
  • PMID: 15548387
    Frohlich M, Albermann N, Sauer A, Walter-Sack I, Haefeli WE, Weiss J: In vitro and ex vivo evidence for modulation of P-glycoprotein activity by progestins. Biochem Pharmacol. 2004 Dec 15;68(12):2409-16. doi: 10.1016/j.bcp.2004.08.026.
  • PMID: 6641224
    Stanczyk FZ, Mroszczak EJ, Ling T, Runkel R, Henzl M, Miyakawa I, Goebelsmann U: Plasma levels and pharmacokinetics of norethindrone and ethinylestradiol administered in solution and as tablets to women. Contraception. 1983 Sep;28(3):241-51. doi: 10.1016/0010-7824(83)90065-3.
  • PMID: 29617576
    Barra F, Scala C, Ferrero S: Current understanding on pharmacokinetics, clinical efficacy and safety of progestins for treating pain associated to endometriosis. Expert Opin Drug Metab Toxicol. 2018 Apr;14(4):399-415. doi: 10.1080/17425255.2018.1461840. Epub 2018 Apr 10.
  • PMID: 11162927
    Schoonen WG, Deckers GH, de Gooijer ME, de Ries R, Kloosterboer HJ: Hormonal properties of norethisterone, 7alpha-methyl-norethisterone and their derivatives. J Steroid Biochem Mol Biol. 2000 Nov 15;74(4):213-22. doi: 10.1016/s0960-0760(00)00125-4.
  • PMID: 19059424
    Walker CJ, Cowan DA, James VH, Lau JC, Kicman AT: Doping in sport: 3. Metabolic conversion of oral norethisterone to urinary 19-norandrosterone. Steroids. 2009 Mar;74(3):341-9. doi: 10.1016/j.steroids.2008.11.008. Epub 2008 Nov 19.
  • PMID: 18356043
    Korhonen T, Turpeinen M, Tolonen A, Laine K, Pelkonen O: Identification of the human cytochrome P450 enzymes involved in the in vitro biotransformation of lynestrenol and norethindrone. J Steroid Biochem Mol Biol. 2008 May;110(1-2):56-66. doi: 10.1016/j.jsbmb.2007.09.025. Epub 2008 Feb 15.
  • PMID: 15063480
    Sitruk-Ware R: Pharmacological profile of progestins. Maturitas. 2004 Apr 15;47(4):277-83.
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