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Identification
Name Levonorgestrel
Accession Number DB00367 (APRD00106, APRD00754, DB00506)
Type small molecule
Groups approved
Description

A synthetic progestational hormone with actions similar to those of progesterone and about twice as potent as its racemic or (+-)-isomer (norgestrel). It is used for contraception, control of menstrual disorders, and treatment of endometriosis. It is usually supplied in a racemic mixture (Norgestrel, 6533-00-2). Only the levonorgestrel isomer is active.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
18-Methylnorethisterone
d(-)-Norgestrel
Levonorgestrelum [INN-Latin]
Salts Not Available
Brand names
Name Company
Jadelle
Levonelle Bayer
Microlut Bayer
Microval
Mirena Bayer
Neogest Schering
Next Choice Watson
Norgeston Bayer
NorLevo Bayer
Norplant
Norplant 2
Norplant II
Ovrette
Plan B
Postinor
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Brand mixtures
Brand Name Ingredients
Alesse Ethinyl Estradiol + Levonorgestrel
Aviane Ethinyl Estradiol + Levonorgestrel
Enpresse Ethinyl Estradiol + Levonorgestrel
Jolessa Ethinyl Estradiol + Levonorgestrel
Lessina Ethinyl Estradiol + Levonorgestrel
Levlen Ethinyl Estradiol + Levonorgestrel
Levora Ethinyl Estradiol + Levonorgestrel
Lo/Ovral Ethinyl Estradiol + Levonorgestrel
Logynon Ethinyl Estradiol + Levonorgestrel
Logynon ED Ethinyl Estradiol + Levonorgestrel
Lutera Ethinyl Estradiol + Levonorgestrel
Lybrel Ethinyl Estradiol + Levonorgestrel
Microgyn Ethinyl Estradiol + Levonorgestrel
Microgynon 30 Ethinyl Estradiol + Levonorgestrel
Microgynon 30 ED Ethinyl Estradiol + Levonorgestrel
Min-Ovral Ethinyl Estradiol + Levonorgestrel
Nordette Ethinyl Estradiol + Levonorgestrel
Nordiol Ethinyl Estradiol + Levonorgestrel
Ovranette Ethinyl Estradiol + Levonorgestrel
Portia Ethinyl Estradiol + Levonorgestrel
Preven Ethinyl Estradiol + Levonorgestrel
Quasense Ethinyl Estradiol + Levonorgestrel
Rigevidon Ethinyl Estradiol + Levonorgestrel
Seasonale Ethinyl Estradiol + Levonorgestrel
Seasonique Ethinyl Estradiol + Levonorgestrel
Sronyx Ethinyl Estradiol + Levonorgestrel
Stediril Ethinyl Estradiol + Levonorgestrel
Tri-Levlen 21 Ethinyl Estradiol + Levonorgestrel
Trifeme 28 Ethinyl Estradiol + Levonorgestrel
Trinordiol Ethinyl Estradiol + Levonorgestrel
Triphasil Ethinyl Estradiol + Levonorgestrel
Triquilar Ethinyl Estradiol + Levonorgestrel
Trivora Ethinyl Estradiol + Levonorgestrel
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Categories
  • Contraceptives
  • Contraceptives, Oral, Synthetic
  • Contraceptive Agents, Female
CAS number 797-63-7
Weight Average: 312.4458
Monoisotopic: 312.20893014
Chemical Formula C21H28O2
InChI Key InChIKey=WWYNJERNGUHSAO-XUDSTZEESA-N
InChI
InChI=1S/C21H28O2/c1-3-20-11-9-17-16-8-6-15(22)13-14(16)5-7-18(17)19(20)10-12-21(20,23)4-2/h2,13,16-19,23H,3,5-12H2,1H3/t16-,17+,18+,19-,20-,21-/m0/s1
Plain Text
IUPAC Name
(1S,2R,10R,11S,14R,15S)-15-ethyl-14-ethynyl-14-hydroxytetracyclo[8.7.0.0^{2,7}.0^{11,15}]heptadec-6-en-5-one
SMILES
[H][C@@]12CC[C@@](O)(C#C)[C@@]1(CC)CC[C@]1([H])[C@@]3([H])CCC(=O)C=C3CC[C@@]21[H]
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Steroids and Steroid Derivatives
Substructures
  • Steroids and Steroid Derivatives
  • Hydroxy Compounds
  • Alkanes and Alkenes
  • Alkynes
  • Alcohols and Polyols
  • Cyclohexenes and Derivatives
  • Ketones
Pharmacology
Indication For the treatment of menopausal and postmenopausal disorders and alone or in combination with other hormones as an oral contraceptive.
Pharmacodynamics Levonorgestrel is a progestin or a synthetic form of the naturally occurring female sex hormone, progesterone. In a woman's normal menstrual cycle, an egg matures and is released from the ovaries (ovulation). The ovary then produces progesterone, preventing the release of further eggs and priming the lining of the womb for a possible pregnancy. If pregnancy occurs, progesterone levels in the body remain high, maintaining the womb lining. If pregnancy does not occur, progesterone levels in the body fall, resulting in a menstrual period. Levonorgestrel tricks the body processes into thinking that ovulation has already occurred, by maintaining high levels of the synthetic progesterone. This prevents the release of eggs from the ovaries.
Mechanism of action Binds to the progesterone and estrogen receptors. Target cells include the female reproductive tract, the mammary gland, the hypothalamus, and the pituitary. Once bound to the receptor, progestins like levonorgestrel will slow the frequency of release of gonadotropin releasing hormone (GnRH) from the hypothalamus and blunt the pre-ovulatory LH (luteinizing hormone) surge.
Absorption Levonorgestrel is not subjected to a "first-pass" effect and is virtually 100% bioavailable.
Volume of distribution
  • 260 L [Healthy Female Volunteers under Fasting Conditions]
  • 1.8 L/kg
Protein binding 55%
Metabolism Hepatic
Route of elimination About 45% of levonorgestrel and its metabolites are excreted in the urine and about 32% are excreted in feces, mostly as glucuronide conjugates.
Half life Not Available
Clearance
  • 7.7 +/- 2.7 L/h [Healthy Female Volunteers under Fasting Conditions]
Toxicity LD50 >5000 mg/kg (orally in rats)
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Wyeth pharmaceuticals inc
  • Population council
  • Population council center for biomedical research
  • Bayer healthcare pharmaceuticals inc
  • Watson laboratories inc
  • Duramed pharmaceuticals inc
Packagers
Dosage forms
Form Route Strength
Insert, extended release Intrauterine
Tablet Oral
Prices
Unit description Cost Unit
Mirena system 843.66 USD each
Mirena System 52 mg Insert 363.54 USD insert
Nordette (28) 28 0.15-30 mg-mcg tablet Disp Pack 79.32 USD disp
Plan b one-step 1.5 mg tablet 40.62 USD tablet
Next choice 0.75 mg tablet 36.56 USD tablet
Levora 0.15/30 (28) 28 0.15-30 mg-mcg tablet Disp Pack 32.99 USD disp
Trivora (28) 28 tablet Box 29.99 USD box
Plan b 0.75 mg tablet 15.65 USD tablet
Nordette-28 tablet 2.75 USD tablet
Nordette-8 tablet 2.39 USD tablet
Levlen 28 tablet 1.3 USD tablet
Tri-levlen 28 tablet 1.25 USD tablet
Levora-28 tablet 1.1 USD tablet
Trivora-28 tablet 0.98 USD tablet
Acidophilus 10 bu/gm granules 0.6 USD g
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DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Country Patent Number Approved Expires (estimated)
United States 5785053 1995-12-05 2015-12-05
Properties
State solid
Experimental Properties
Property Value Source
melting point 240 °C PhysProp
water solubility 2.05 mg/L Not Available
logP 3.8 Not Available
Predicted Properties
Property Value Source
water solubility 5.83e-03 g/l ALOGPS
logP 3.25 ALOGPS
logP 3.66 ChemAxon
logS -4.7 ALOGPS
pKa (strongest acidic) 17.91 ChemAxon
pKa (strongest basic) -1.5 ChemAxon
physiological charge 0 ChemAxon
hydrogen acceptor count 2 ChemAxon
hydrogen donor count 1 ChemAxon
polar surface area 37.3 ChemAxon
rotatable bond count 1 ChemAxon
refractivity 92.03 ChemAxon
polarizability 36.73 ChemAxon
References
Synthesis Reference Not Available
General Reference
  1. Edgren RA, Stanczyk FZ: Nomenclature of the gonane progestins. Contraception. 1999 Dec;60(6):313. Pubmed
  2. Sitruk-Ware R: New progestagens for contraceptive use. Hum Reprod Update. 2006 Mar-Apr;12(2):169-78. Epub 2005 Nov 16. Pubmed
External Links
Resource Link
KEGG Drug D00950 Link_out
KEGG Compound C08149 Link_out
PubChem Compound 13109 Link_out
PubChem Substance 46508082 Link_out
ChemSpider 12560 Link_out
ChEBI 6443 Link_out
ChEMBL 6443 Link_out
Therapeutic Targets Database DAP001207 Link_out
PharmGKB PA450656 Link_out
IUPHAR 2881 Link_out
Guide to Pharmacology 2881 Link_out
Drug Product Database 707600 Link_out
RxList http://www.rxlist.com/cgi/generic2/norplant.htm Link_out
Drugs.com http://www.drugs.com/cdi/levonorgestrel.html Link_out
PDRhealth http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/pla1696.shtml Link_out
Wikipedia http://en.wikipedia.org/wiki/Levonorgestrel Link_out
ATC Codes
  • G03AC03
  • G03AD01
AHFS Codes
  • 68:12.00
PDB Entries Not Available
FDA label show (8.04 KB)
MSDS show (19.7 KB)
Interactions
Drug Interactions
Drug Interaction
Amobarbital Phenobarbital decreases the effect of levonorgestrel
Aprobarbital Phenobarbital decreases the effect of levonorgestrel
Artemether Artemether may decrease the effectiveness of levonorgestrel by increasing its metabolism via CYP3A4. Consider an alternate non-hormonal means of contraception during artemether therapy.
Bexarotene Bexarotene may decrease the serum concentration of Contraceptives (Progestins). Since bexarotene is teratogenic and can lower serum concentrations of levonorgestrel, it is advised that women of childbearing potential use two forms of contraception (including at least one non-hormonal form).
Butabarbital Phenobarbital decreases the effect of levonorgestrel
Butalbital Phenobarbital decreases the effect of levonorgestrel
Butethal Phenobarbital decreases the effect of levonorgestrel
Carbamazepine Carbamazepine may decrease the contraceptive effect of levonorgestrel.
Colesevelam Bile Acid Sequestrants may decrease the serum concentration of Contraceptives (Progestins). Administer oral progestin-containing contraceptives at least 1-4 hours prior to or 4-6 hours after administration of a bile acid sequestrant. Consider alternatives in order to avoid this combination when possible, due to the risk for impaired contraceptive effectiveness.
Dihydroquinidine barbiturate Phenobarbital decreases the effect of levonorgestrel
Ethotoin Phenytoin decreases the contraceptive effect
Fosphenytoin Phenytoin decreases the contraceptive effect
Heptabarbital Phenobarbital decreases the effect of levonorgestrel
Hexobarbital Phenobarbital decreases the effect of levonorgestrel
Mephenytoin Phenytoin decreases the contraceptive effect
Methohexital Phenobarbital decreases the effect of levonorgestrel
Methylphenobarbital Phenobarbital decreases the effect of levonorgestrel
Pentobarbital Phenobarbital decreases the effect of levonorgestrel
Phenobarbital Phenobarbital decreases the effect of levonorgestrel
Phenytoin Phenytoin decreases the contraceptive effect
Primidone Phenobarbital decreases the effect of levonorgestrel
Quinidine barbiturate Phenobarbital decreases the effect of levonorgestrel
Secobarbital Phenobarbital decreases the effect of levonorgestrel
Talbutal Phenobarbital decreases the effect of levonorgestrel
Thiopental Thiopental may decrease the effect of Levonorgestrel. Contraceptive failure may occur. Alternative nonhomomonal contraception should be used during concomitant therapy.
Tretinoin Oral Tretinoin may decrease the effect of oral contraceptive, Levonorgestrel. An alternate form of contraception should be used during concomitant therapy.
Warfarin Levonorgestrel may alter the anticoagulant effect of warfarin. Concomitant therapy should be avoided. Monitor for changes in coagulation status if levonorgestrel is initiated, discontinued or dose changed.
Food Interactions
  • Avoid alcohol.
  • Avoid excessive quantities of coffee or tea (Caffeine).
  • Increase dietary intake of magnesium, folate, vitamin B6, B12, and/or consider taking a multivitamin.
  • Take at the same time everyday.
  • Take with food.
Targets

1. Progesterone receptor

Pharmacological action: yes
Actions: binder

The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues

Organism class: human
UniProt ID: P06401 Link_out
Gene: PGR Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Maruo T, Ohara N, Matsuo H, Xu Q, Chen W, Sitruk-Ware R, Johansson ED: Effects of levonorgestrel-releasing IUS and progesterone receptor modulator PRM CDB-2914 on uterine leiomyomas. Contraception. 2007 Jun;75(6 Suppl):S99-103. Epub 2007 Mar 21. Pubmed
  2. Mirkin S, Wong BC, Archer DF: Effect of 17 beta-estradiol, progesterone, synthetic progestins, tibolone, and tibolone metabolites on vascular endothelial growth factor mRNA in breast cancer cells. Fertil Steril. 2005 Aug;84(2):485-91. Pubmed
  3. Hompes PG, Mijatovic V: Endometriosis: the way forward. Gynecol Endocrinol. 2007 Jan;23(1):5-12. Pubmed
  4. Creinin MD, Schlaff W, Archer DF, Wan L, Frezieres R, Thomas M, Rosenberg M, Higgins J: Progesterone receptor modulator for emergency contraception: a randomized controlled trial. Obstet Gynecol. 2006 Nov;108(5):1089-97. Pubmed
  5. Bray JD, Jelinsky S, Ghatge R, Bray JA, Tunkey C, Saraf K, Jacobsen BM, Richer JK, Brown EL, Winneker RC, Horwitz KB, Lyttle CR: Quantitative analysis of gene regulation by seven clinically relevant progestins suggests a highly similar mechanism of action through progesterone receptors in T47D breast cancer cells. J Steroid Biochem Mol Biol. 2005 Dec;97(4):328-41. Epub 2005 Sep 12. Pubmed
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. 3-oxo-5-alpha-steroid 4-dehydrogenase 1

Pharmacological action: yes
Actions: inhibitor

Converts testosterone into 5-alpha-dihydrotestosterone and progesterone or corticosterone into their corresponding 5- alpha-3-oxosteroids. It plays a central role in sexual differentiation and androgen physiology

Organism class: human
UniProt ID: P18405 Link_out
Gene: SRD5A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Hammond GL, Rabe T, Wagner JD: Preclinical profiles of progestins used in formulations of oral contraceptives and hormone replacement therapy. Am J Obstet Gynecol. 2001 Aug;185(2 Suppl):S24-31. Pubmed
  2. Rabe T, Kowald A, Ortmann J, Rehberger-Schneider S: Inhibition of skin 5 alpha-reductase by oral contraceptive progestins in vitro. Gynecol Endocrinol. 2000 Aug;14(4):223-30. Pubmed

3. Estrogen receptor

Pharmacological action: yes
Actions: other

Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues

Organism class: human
UniProt ID: P03372 Link_out
Gene: ESR1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Vereide AB, Kaino T, Sager G, Arnes M, Orbo A: Effect of levonorgestrel IUD and oral medroxyprogesterone acetate on glandular and stromal progesterone receptors (PRA and PRB), and estrogen receptors (ER-alpha and ER-beta) in human endometrial hyperplasia. Gynecol Oncol. 2006 May;101(2):214-23. Epub 2005 Dec 1. Pubmed
  2. Mirkin S, Wong BC, Archer DF: Effect of 17 beta-estradiol, progesterone, synthetic progestins, tibolone, and tibolone metabolites on vascular endothelial growth factor mRNA in breast cancer cells. Fertil Steril. 2005 Aug;84(2):485-91. Pubmed
  3. Abdel-Aleem H, Shaaban OM, Amin AF, Abdel-Aleem AM: Tamoxifen treatment of bleeding irregularities associated with Norplant use. Contraception. 2005 Dec;72(6):432-7. Epub 2005 Aug 9. Pubmed
  4. Sun D, Yan C, Jacobson A, Jiang H, Carroll MA, Huang A: Contribution of epoxyeicosatrienoic acids to flow-induced dilation in arteries of male ERalpha knockout mice: role of aromatase. Am J Physiol Regul Integr Comp Physiol. 2007 Sep;293(3):R1239-46. Epub 2007 Jul 18. Pubmed
  5. Vijayanathan V, Venkiteswaran S, Nair SK, Verma A, Thomas TJ, Zhu BT, Thomas T: Physiologic levels of 2-methoxyestradiol interfere with nongenomic signaling of 17beta-estradiol in human breast cancer cells. Clin Cancer Res. 2006 Apr 1;12(7 Pt 1):2038-48. Pubmed

4. Androgen receptor

Pharmacological action: unknown
Actions: agonist

The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Activated, but not phosphorylated, by HIPK3

Organism class: human
UniProt ID: P10275 Link_out
Gene: AR Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Shields-Botella J, Duc I, Duranti E, Puccio F, Bonnet P, Delansorne R, Paris J: An overview of nomegestrol acetate selective receptor binding and lack of estrogenic action on hormone-dependent cancer cells. J Steroid Biochem Mol Biol. 2003 Nov;87(2-3):111-22. Pubmed
  2. Freyberger A, Witters H, Weimer M, Lofink W, Berckmans P, Ahr HJ: Screening for (anti)androgenic properties using a standard operation protocol based on the human stably transfected androgen sensitive PALM cell line. First steps towards validation. Reprod Toxicol. 2010 Aug;30(1):9-17. Epub 2009 Oct 27. Pubmed
  3. Freyberger A, Weimer M, Tran HS, Ahr HJ: Assessment of a recombinant androgen receptor binding assay: initial steps towards validation. Reprod Toxicol. 2010 Aug;30(1):2-8. Epub 2009 Oct 13. Pubmed
  4. Kloosterboer HJ, Vonk-Noordegraaf CA, Turpijn EW: Selectivity in progesterone and androgen receptor binding of progestagens used in oral contraceptives. Contraception. 1988 Sep;38(3):325-32. Pubmed
Enzymes

1. Cytochrome P450 3A4

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

2. Cytochrome P450 19A1

Actions: inhibitor

Catalyzes the formation of aromatic C18 estrogens from C19 androgens

UniProt ID: P11511 Link_out
Gene: CYP19A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:19