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Identification
NameMifepristone
Accession NumberDB00834  (APRD00432)
Typesmall molecule
Groupsapproved, investigational
Description

A progestational and glucocorticoid hormone antagonist. Its inhibition of progesterone induces bleeding during the luteal phase and in early pregnancy by releasing endogenous prostaglandins from the endometrium or decidua. As a glucocorticoid receptor antagonist, the drug has been used to treat hypercortisolism in patients with nonpituitary cushing syndrome [PubChem]. The two marketed forms of mifepristone are Mifeprex® (mifepristone 200mg) and Korlym™ (mifepristone 300mg). Currently under investigation for use in psychotic depression (phase 3 trials).

Structure
Thumb
Synonyms
SynonymLanguageCode
MifepristonGermanINN
MifepristonaSpanishINN
MifépristoneFrenchINN
MifepristonumLatinINN
SaltsNot Available
Brand names
NameCompany
CorluxCorcept Therapeutics Incorporated
KorlymCorcept Therapeutics
MefipilAbbott
MifegyneExelgyn Laboratories
MifeprexDanco Laboratories
Brand mixturesNot Available
Categories
CAS number84371-65-3
WeightAverage: 429.5937
Monoisotopic: 429.266779369
Chemical FormulaC29H35NO2
InChI KeyInChIKey=VKHAHZOOUSRJNA-GCNJZUOMSA-N
InChI
InChI=1S/C29H35NO2/c1-5-15-29(32)16-14-26-24-12-8-20-17-22(31)11-13-23(20)27(24)25(18-28(26,29)2)19-6-9-21(10-7-19)30(3)4/h6-7,9-10,17,24-26,32H,8,11-14,16,18H2,1-4H3/t24-,25+,26-,28-,29-/m0/s1
IUPAC Name
(10S,11S,14S,15S,17R)-17-[4-(dimethylamino)phenyl]-14-hydroxy-15-methyl-14-(prop-1-yn-1-yl)tetracyclo[8.7.0.0^{2,7}.0^{11,15}]heptadeca-1,6-dien-5-one
SMILES
[H][C@@]12CC[C@@](O)(C#CC)[C@@]1(C)C[C@H](C1=CC=C(C=C1)N(C)C)C1=C3CCC(=O)C=C3CC[C@@]21[H]
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassLipids
ClassSteroids and Steroid Derivatives
SubclassKetosteroids
Direct parentKetosteroids
Alternative parentsHydroxysteroids; Ynones; Benzene and Substituted Derivatives; Tertiary Alcohols; Tertiary Amines; Cyclic Alcohols and Derivatives; Polyamines
Substituentsynone; benzene; cyclic alcohol; tertiary alcohol; tertiary amine; ketone; polyamine; organonitrogen compound; amine; 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 medical termination of intrauterine pregnancy through 49 days' pregnancy. Also indicated to control hyperglycemia secondary to hypercortisolism in adult patients with endogenous Cushing's syndrome who have type 2 diabetes mellitus or glucose intolerance and are not candidates for surgery or have had unsuccessful surgery.
PharmacodynamicsMifepristone is a synthetic steroid with antiprogestational effects indicated for the medical termination of intrauterine pregnancy through 49 days' pregnancy. Doses of 1 mg/kg or greater of mifepristone have been shown to antagonize the endometrial and myometrial effects of progesterone in women. During pregnancy, the compound sensitizes the myometrium to the contraction-inducing activity of prostaglandins. Mifepristone also exhibits antiglucocorticoid and weak antiandrogenic activity. The activity of the glucocorticoid dexamethasone in rats was inhibited following doses of 10 to 25 mg/kg of mifepristone. Doses of 4.5 mg/kg or greater in human beings resulted in a compensatory elevation of adrenocorticotropic hormone (ACTH) and cortisol.
Mechanism of actionThe anti-progestational activity of mifepristone results from competitive interaction with progesterone at progesterone-receptor sites. Based on studies with various oral doses in several animal species (mouse, rat, rabbit and monkey), the compound inhibits the activity of endogenous or exogenous progesterone. The termination of pregnancy results. In the treatment of Cushing's syndrome, Mifepristone blocks the binding of cortisol to its receptor. It does not decrease cortisol production but reduces the effects of excess cortisol, such as high blood sugar levels.
AbsorptionThe absolute bioavailability of a 20 mg oral dose is 69%
Volume of distributionNot Available
Protein binding98% (bound to plasma proteins, albumin and a 1-acid glycoprotein)
Metabolism

Hepatic. Hepatic, by Cytochrome P450 3A4 isoenzyme to the N-monodemethylated metabolite (RU 42 633); RU 42 698, which results from the loss of two methyl groups from position 11 beta; and RU 42 698, which results from terminal hydroxylation of the 17–propynyl chain.

Route of eliminationFecal: 83%; Renal: 9%.
Half life18 hours
ClearanceNot Available
ToxicityNearly all of the women who receive mifepristone will report adverse reactions, and many can be expected to report more than one such reaction. About 90% of patients report adverse reactions following administration of misoprostol on day three of the treatment procedure. Side effects include more heavy bleeding than a heavy menstrual period, abdominal pain, uterine cramping, nausea, vomiting, and diarrhea.
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 + 0.7135
Caco-2 permeable + 0.6716
P-glycoprotein substrate Substrate 0.643
P-glycoprotein inhibitor I Inhibitor 0.8564
P-glycoprotein inhibitor II Inhibitor 0.8387
Renal organic cation transporter Non-inhibitor 0.8177
CYP450 2C9 substrate Non-substrate 0.7606
CYP450 2D6 substrate Non-substrate 0.9116
CYP450 3A4 substrate Substrate 0.8334
CYP450 1A2 substrate Inhibitor 0.9106
CYP450 2C9 substrate Non-inhibitor 0.6293
CYP450 2D6 substrate Inhibitor 0.8931
CYP450 2C19 substrate Inhibitor 0.8994
CYP450 3A4 substrate Inhibitor 0.796
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.6129
Ames test Non AMES toxic 0.856
Carcinogenicity Non-carcinogens 0.825
Biodegradation Not ready biodegradable 0.9971
Rat acute toxicity 2.7705 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9177
hERG inhibition (predictor II) Non-inhibitor 0.6879
Pharmacoeconomics
Manufacturers
  • Danco laboratories llc
Packagers
  • Danco Labs LLC
Dosage forms
FormRouteStrength
TabletOral200mg
TabletOral300mg
Prices
Unit descriptionCostUnit
Mifeprex 200 mg tablet90.0USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point191-196 °CFDA Label
water solubilityPoorly solubleFDA Label
logP4.5Not Available
Predicted Properties
PropertyValueSource
water solubility3.36e-03 g/lALOGPS
logP5.33ALOGPS
logP5.13ChemAxon
logS-5.1ALOGPS
pKa (strongest acidic)12.87ChemAxon
pKa (strongest basic)4.89ChemAxon
physiological charge0ChemAxon
hydrogen acceptor count3ChemAxon
hydrogen donor count1ChemAxon
polar surface area40.54ChemAxon
rotatable bond count3ChemAxon
refractivity132.58ChemAxon
polarizability50.71ChemAxon
number of rings5ChemAxon
bioavailability1ChemAxon
rule of fiveNoChemAxon
Ghose filterNoChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Narendra Joshi, Anil Khile, Nitin Pradhan, “Novel polymorph form M of mifepristone and process for its preparation.” U.S. Patent US20070105828, issued May 10, 2007.

US20070105828
General Reference
  1. Fiala C, Gemzel-Danielsson K: Review of medical abortion using mifepristone in combination with a prostaglandin analogue. Contraception. 2006 Jul;74(1):66-86. Epub 2006 May 19. Pubmed
  2. Heikinheimo O, Kekkonen R, Lahteenmaki P: The pharmacokinetics of mifepristone in humans reveal insights into differential mechanisms of antiprogestin action. Contraception. 2003 Dec;68(6):421-6. Pubmed
  3. Chabbert-Buffet N, Meduri G, Bouchard P, Spitz IM: Selective progesterone receptor modulators and progesterone antagonists: mechanisms of action and clinical applications. Hum Reprod Update. 2005 May-Jun;11(3):293-307. Epub 2005 Mar 24. Pubmed
  4. Spitz IM, Bardin CW, Benton L, Robbins A: Early pregnancy termination with mifepristone and misoprostol in the United States. N Engl J Med. 1998 Apr 30;338(18):1241-7. Pubmed
  5. Piaggio G, von Hertzen H, Heng Z, Bilian X, Cheng L: Meta-analyses of randomized trials comparing different doses of mifepristone in emergency contraception. Contraception. 2003 Dec;68(6):447-52. Pubmed
External Links
ResourceLink
KEGG DrugD00585
KEGG CompoundC07652
PubChem Compound55245
PubChem Substance46505795
ChemSpider49889
BindingDB18627
ChEBI50692
ChEMBLCHEMBL1276308
Therapeutic Targets DatabaseDAP000090
PharmGKBPA450500
IUPHAR2805
Guide to Pharmacology2805
HET486
RxListhttp://www.rxlist.com/cgi/generic3/mifeprist.htm
Drugs.comhttp://www.drugs.com/cdi/mifepristone.html
WikipediaMifepristone
ATC CodesG03XB01
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelshow(46.5 KB)
MSDSshow(57.1 KB)
Interactions
Drug Interactions
Drug
Dabigatran etexilateMay lead to excessive post-abortion bleeding in patients on anticoagulant therapy. Concomitant therapy is contraindicated.
DegarelixEnhance QTc-prolonging effect
EtravirineMifepristone, when used concomitantly with etravirine (a strong CYP3A4 inducer), may experience a decrease in serum concentration. It is recommended to avoid concurrent therapy.
PasireotideAvoid combination with mifepristone and other moderate to high risk QTc prolonging agents. The combinaton may enhance the QTc-prolonging effect of these drugs.
TofacitinibMifepristone, when used in combination with tofacitinib, may increase tofacitinib concentrations. It is recommended to adjust therapy by using a minimized dose of tofacitinib, and monitoring for increased tofacitinib concentrations and signs of toxicity, during and 2 weeks after discontinuation of mifepristone therapy.
Food InteractionsNot Available

1. Progesterone receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
Progesterone receptor P06401 Details

References:

  1. Greb RR, Kiesel L, Selbmann AK, Wehrmann M, Hodgen GD, Goodman AL, Wallwiener D: Disparate actions of mifepristone (RU 486) on glands and stroma in the primate endometrium. Hum Reprod. 1999 Jan;14(1):198-206. Pubmed
  2. Sun M, Zhu G, Zhou L: [Effect of mifepristone on the expression of progesterone receptor messenger RNA and protein in uterine leiomyomata] Zhonghua Fu Chan Ke Za Zhi. 1998 Apr;33(4):227-31. Pubmed
  3. Hazra BG, Basu S, Pore VS, Joshi PL, Pal D, Chakrabarti P: Synthesis of 11beta-(4-dimethylaminophenyl)-17beta-hydroxy-17alpha- (3-methyl-1-butynyl)-4, 9-estradien-3-one and 11beta-(4-acetophenyl)- 17beta-hydroxy-17alpha-(3-methyl-1-butynyl)-4, 9-estradien-3-one: two new analogs of mifepristone (RU-486). Steroids. 2000 Mar;65(3):157-62. Pubmed
  4. Gao Y, Cheng L, Liu Y: [Failure of mifepristone induced interruption of pregnancy: point mutation at genetic codon 722 in human progesterone receptor gene] Zhonghua Fu Chan Ke Za Zhi. 1998 Sep;33(9):549-52. Pubmed
  5. Jiang J, Wu R, Wang Z: [Effects of mifepristone on expression of estrogen receptor and progesterone receptor in cultured human eutopic and ectopic endometria] Zhonghua Fu Chan Ke Za Zhi. 2001 Apr;36(4):218-21. Pubmed
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. Glucocorticoid receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
Glucocorticoid receptor P04150 Details

References:

  1. LeVan TD, Babin EA, Yamamura HI, Bloom JW: Pharmacological characterization of glucocorticoid receptors in primary human bronchial epithelial cells. Biochem Pharmacol. 1999 May 1;57(9):1003-9. Pubmed
  2. Attardi BJ, Burgenson J, Hild SA, Reel JR: In vitro antiprogestational/antiglucocorticoid activity and progestin and glucocorticoid receptor binding of the putative metabolites and synthetic derivatives of CDB-2914, CDB-4124, and mifepristone. J Steroid Biochem Mol Biol. 2004 Mar;88(3):277-88. Pubmed
  3. Aida K, Shi Q, Wang J, VandeBerg JL, McDonald T, Nathanielsz P, Wang XL: The effects of betamethasone (BM) on endothelial nitric oxide synthase (eNOS) expression in adult baboon femoral arterial endothelial cells. J Steroid Biochem Mol Biol. 2004 Aug;91(4-5):219-24. Pubmed
  4. Gu G, Hentunen TA, Nars M, Harkonen PL, Vaananen HK: Estrogen protects primary osteocytes against glucocorticoid-induced apoptosis. Apoptosis. 2005 May;10(3):583-95. Pubmed
  5. de Pablos RM, Villaran RF, Arguelles S, Herrera AJ, Venero JL, Ayala A, Cano J, Machado A: Stress increases vulnerability to inflammation in the rat prefrontal cortex. J Neurosci. 2006 May 24;26(21):5709-19. Pubmed

1. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor inducer

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  2. 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 3A5

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Cytochrome P450 3A5 P20815 Details

References:

  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  2. 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

3. Cytochrome P450 3A7

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 3A7 P24462 Details

References:

  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  2. 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

4. Cytochrome P450 2D6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2D6 P10635 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

1. Multidrug resistance protein 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor inducer

Components

Name UniProt ID Details
Multidrug resistance protein 1 P08183 Details

References:

  1. Geick A, Eichelbaum M, Burk O: Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. J Biol Chem. 2001 May 4;276(18):14581-7. Epub 2001 Jan 31. Pubmed
  2. Lecureur V, Fardel O, Guillouzo A: The antiprogestatin drug RU 486 potentiates doxorubicin cytotoxicity in multidrug resistant cells through inhibition of P-glycoprotein function. FEBS Lett. 1994 Nov 28;355(2):187-91. Pubmed

2. Multidrug resistance-associated protein 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Multidrug resistance-associated protein 1 P33527 Details

References:

  1. Payen L, Delugin L, Courtois A, Trinquart Y, Guillouzo A, Fardel O: Reversal of MRP-mediated multidrug resistance in human lung cancer cells by the antiprogestatin drug RU486. Biochem Biophys Res Commun. 1999 May 19;258(3):513-8. Pubmed

Comments
Drug created on June 13, 2005 07:24 / Updated on October 29, 2013 15:39