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Identification
NameLevonorgestrel
Accession NumberDB00367  (APRD00106, APRD00754, DB00506)
Typesmall molecule
Groupsapproved, investigational
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. Levonorgestrel is marketed mostly as a combination oral contraceptive under several brand names such as Alesse, Triphasil, and Min-Ovral.

Structure
Thumb
Synonyms
SynonymLanguageCode
(8R,9S,10R,13S,14S,17R)-13-ethyl-17-ethynyl-17-hydroxy- 1,2,6,7,8,9,10,11,12,13,14,15,16, 17- tetradecahydrocyclopenta[a] phenanthren-3-oneNot AvailableIUPAC
18-MethylnorethisteroneNot AvailableNot Available
d(-)-NorgestrelNot AvailableNot Available
LevonorgestrelNot AvailableBAN, DCIT, USAN, BP 2011, Ph. Eur. 7, Ph. Int. 4, USP 34
LévonorgestrelNot AvailableDCF
LevonorgestrelumLatinINN
SaltsNot Available
Brand names
NameCompany
JadelleBayer
LevonelleBayer
MedonorMedopharm
MicrolutBayer
MicrovalWyeth
MirenaBayer
NeogestSchering
Next ChoiceWatson
NorgestonBayer
NorLevoBayer
NorplantBayer
Plan BTeva
PostinorGedeon Richter
Brand mixtures
Brand NameIngredients
AlesseEthinyl Estradiol + Levonorgestrel
AvianeEthinyl Estradiol + Levonorgestrel
EnpresseEthinyl Estradiol + Levonorgestrel
JolessaEthinyl Estradiol + Levonorgestrel
LessinaEthinyl Estradiol + Levonorgestrel
LevlenEthinyl Estradiol + Levonorgestrel
LevoraEthinyl Estradiol + Levonorgestrel
Lo/OvralEthinyl Estradiol + Levonorgestrel
LogynonEthinyl Estradiol + Levonorgestrel
Logynon EDEthinyl Estradiol + Levonorgestrel
LuteraEthinyl Estradiol + Levonorgestrel
LybrelEthinyl Estradiol + Levonorgestrel
MicrogynEthinyl Estradiol + Levonorgestrel
Microgynon 30Ethinyl Estradiol + Levonorgestrel
Microgynon 30 EDEthinyl Estradiol + Levonorgestrel
Min-OvralEthinyl Estradiol + Levonorgestrel
NordetteEthinyl Estradiol + Levonorgestrel
NordiolEthinyl Estradiol + Levonorgestrel
OvranetteEthinyl Estradiol + Levonorgestrel
PortiaEthinyl Estradiol + Levonorgestrel
PrevenEthinyl Estradiol + Levonorgestrel
QuartetteLevonorgestrel/Ethinyl Estradiol + Ethinyl Estradiol
QuasenseEthinyl Estradiol + Levonorgestrel
RigevidonEthinyl Estradiol + Levonorgestrel
SeasonaleEthinyl Estradiol + Levonorgestrel
SeasoniqueEthinyl Estradiol + Levonorgestrel
SronyxEthinyl Estradiol + Levonorgestrel
StedirilEthinyl Estradiol + Levonorgestrel
Tri-Levlen 21Ethinyl Estradiol + Levonorgestrel
Trifeme 28Ethinyl Estradiol + Levonorgestrel
TrinordiolEthinyl Estradiol + Levonorgestrel
TriphasilEthinyl Estradiol + Levonorgestrel
TriquilarEthinyl Estradiol + Levonorgestrel
TrivoraEthinyl Estradiol + Levonorgestrel
Categories
CAS number797-63-7
WeightAverage: 312.4458
Monoisotopic: 312.20893014
Chemical FormulaC21H28O2
InChI KeyInChIKey=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
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]
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassLipids
ClassSteroids and Steroid Derivatives
SubclassKetosteroids
Direct parentKetosteroids
Alternative parentsHydroxysteroids; Estrogens and Derivatives; Ynones; Tertiary Alcohols; Cyclic Alcohols and Derivatives; Polyamines
Substituentsynone; tertiary alcohol; cyclic alcohol; ketone; polyamine; alcohol; carbonyl group
Classification descriptionThis compound belongs to the ketosteroids. These are steroid derivatives comprising a ketone group attached to steroid skeleton.
Pharmacology
IndicationFor the treatment of menopausal and postmenopausal disorders and alone or in combination with other hormones as an oral contraceptive.
PharmacodynamicsLevonorgestrel 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 actionBinds 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.
AbsorptionLevonorgestrel 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 binding55%
Metabolism

Hepatic

Route of eliminationAbout 45% of levonorgestrel and its metabolites are excreted in the urine and about 32% are excreted in feces, mostly as glucuronide conjugates.
Half lifeNot Available
Clearance
  • 7.7 +/- 2.7 L/h [Healthy Female Volunteers under Fasting Conditions]
ToxicityLD50 >5000 mg/kg (orally in rats)
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 1.0
Blood Brain Barrier + 0.9453
Caco-2 permeable + 0.8094
P-glycoprotein substrate Substrate 0.6648
P-glycoprotein inhibitor I Inhibitor 0.5
P-glycoprotein inhibitor II Non-inhibitor 0.8382
Renal organic cation transporter Non-inhibitor 0.7697
CYP450 2C9 substrate Non-substrate 0.7904
CYP450 2D6 substrate Non-substrate 0.9165
CYP450 3A4 substrate Substrate 0.7239
CYP450 1A2 substrate Non-inhibitor 0.9045
CYP450 2C9 substrate Non-inhibitor 0.907
CYP450 2D6 substrate Non-inhibitor 0.9232
CYP450 2C19 substrate Inhibitor 0.8994
CYP450 3A4 substrate Non-inhibitor 0.7772
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.516
Ames test Non AMES toxic 0.9132
Carcinogenicity Non-carcinogens 0.9328
Biodegradation Not ready biodegradable 0.9814
Rat acute toxicity 1.8264 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.8205
hERG inhibition (predictor II) Non-inhibitor 0.7408
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
FormRouteStrength
Insert, extended releaseIntrauterine
TabletOral
Prices
Unit descriptionCostUnit
Mirena system843.66USDeach
Mirena System 52 mg Insert363.54USDinsert
Nordette (28) 28 0.15-30 mg-mcg tablet Disp Pack79.32USDdisp
Plan b one-step 1.5 mg tablet40.62USDtablet
Next choice 0.75 mg tablet36.56USDtablet
Levora 0.15/30 (28) 28 0.15-30 mg-mcg tablet Disp Pack32.99USDdisp
Trivora (28) 28 tablet Box29.99USDbox
Plan b 0.75 mg tablet15.65USDtablet
Nordette-28 tablet2.75USDtablet
Nordette-8 tablet2.39USDtablet
Levlen 28 tablet1.3USDtablet
Tri-levlen 28 tablet1.25USDtablet
Levora-28 tablet1.1USDtablet
Trivora-28 tablet0.98USDtablet
Acidophilus 10 bu/gm granules0.6USDg
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States57850531995-12-052015-12-05
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point240 °CPhysProp
water solubility2.05 mg/LNot Available
logP3.8Not Available
Predicted Properties
PropertyValueSource
water solubility5.83e-03 g/lALOGPS
logP3.25ALOGPS
logP3.66ChemAxon
logS-4.7ALOGPS
pKa (strongest acidic)17.91ChemAxon
pKa (strongest basic)-1.5ChemAxon
physiological charge0ChemAxon
hydrogen acceptor count2ChemAxon
hydrogen donor count1ChemAxon
polar surface area37.3ChemAxon
rotatable bond count1ChemAxon
refractivity92.03ChemAxon
polarizability36.73ChemAxon
number of rings4ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleYesChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Yu-Sheng Chang, Shu-Ping Chen, “Levonorgestrel Crystallization.” U.S. Patent US20090069584, issued March 12, 2009.

US20090069584
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
  3. FDA label.
External Links
ResourceLink
KEGG DrugD00950
KEGG CompoundC08149
PubChem Compound13109
PubChem Substance46508082
ChemSpider12560
ChEBI6443
ChEMBLCHEMBL1389
Therapeutic Targets DatabaseDAP001207
PharmGKBPA450656
IUPHAR2881
Guide to Pharmacology2881
Drug Product Database707600
RxListhttp://www.rxlist.com/cgi/generic2/norplant.htm
Drugs.comhttp://www.drugs.com/cdi/levonorgestrel.html
PDRhealthhttp://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/pla1696.shtml
WikipediaLevonorgestrel
ATC CodesG03AC03G03AD01
AHFS Codes
  • 68:12.00
PDB EntriesNot Available
FDA labelshow(8.04 KB)
MSDSshow(19.7 KB)
Interactions
Drug Interactions
Drug
AmobarbitalPhenobarbital decreases the effect of levonorgestrel
AprobarbitalPhenobarbital decreases the effect of levonorgestrel
ArtemetherArtemether may decrease the effectiveness of levonorgestrel by increasing its metabolism via CYP3A4. Consider an alternate non-hormonal means of contraception during artemether therapy.
BexaroteneBexarotene 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).
ButabarbitalPhenobarbital decreases the effect of levonorgestrel
ButalbitalPhenobarbital decreases the effect of levonorgestrel
ButethalPhenobarbital decreases the effect of levonorgestrel
CarbamazepineCarbamazepine may decrease the contraceptive effect of levonorgestrel.
ColesevelamBile 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 barbituratePhenobarbital decreases the effect of levonorgestrel
EthotoinPhenytoin decreases the contraceptive effect
FosphenytoinPhenytoin decreases the contraceptive effect
HeptabarbitalPhenobarbital decreases the effect of levonorgestrel
HexobarbitalPhenobarbital decreases the effect of levonorgestrel
MephenytoinPhenytoin decreases the contraceptive effect
MethohexitalPhenobarbital decreases the effect of levonorgestrel
MethylphenobarbitalPhenobarbital decreases the effect of levonorgestrel
PentobarbitalPhenobarbital decreases the effect of levonorgestrel
PhenobarbitalPhenobarbital decreases the effect of levonorgestrel
PhenytoinPhenytoin decreases the contraceptive effect
PrimidonePhenobarbital decreases the effect of levonorgestrel
Quinidine barbituratePhenobarbital decreases the effect of levonorgestrel
SecobarbitalPhenobarbital decreases the effect of levonorgestrel
TalbutalPhenobarbital decreases the effect of levonorgestrel
ThiopentalThiopental may decrease the effect of Levonorgestrel. Contraceptive failure may occur. Alternative nonhomomonal contraception should be used during concomitant therapy.
TretinoinOral Tretinoin may decrease the effect of oral contraceptive, Levonorgestrel. An alternate form of contraception should be used during concomitant therapy.
WarfarinLevonorgestrel 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.

1. Progesterone receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: binder

Components

Name UniProt ID Details
Progesterone receptor P06401 Details

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

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
3-oxo-5-alpha-steroid 4-dehydrogenase 1 P18405 Details

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

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: other

Components

Name UniProt ID Details
Estrogen receptor P03372 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: agonist

Components

Name UniProt ID Details
Androgen receptor P10275 Details

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

1. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 19A1 P11511 Details

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 September 16, 2013 17:10