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Identification
NameDanazol
Accession NumberDB01406
Typesmall molecule
Groupsapproved
Description

A synthetic steroid with antigonadotropic and anti-estrogenic activities that acts as an anterior pituitary suppressant by inhibiting the pituitary output of gonadotropins. It possesses some androgenic properties. Danazol has been used in the treatment of endometriosis and some benign breast disorders. [PubChem]

Structure
Thumb
SynonymsNot Available
SaltsNot Available
Brand names
NameCompany
CyclomenNot Available
DanocrineNot Available
Brand mixturesNot Available
CategoriesNot Available
CAS number17230-88-5
WeightAverage: 337.4553
Monoisotopic: 337.204179113
Chemical FormulaC22H27NO2
InChI KeyInChIKey=POZRVZJJTULAOH-LHZXLZLDSA-N
InChI
InChI=1S/C22H27NO2/c1-4-22(24)10-8-18-16-6-5-15-11-19-14(13-23-25-19)12-20(15,2)17(16)7-9-21(18,22)3/h1,11,13,16-18,24H,5-10,12H2,2-3H3/t16-,17+,18+,20+,21+,22+/m1/s1
IUPAC Name
(1S,2R,13R,14S,17R,18S)-17-ethynyl-2,18-dimethyl-7-oxa-6-azapentacyclo[11.7.0.0^{2,10}.0^{4,8}.0^{14,18}]icosa-4(8),5,9-trien-17-ol
SMILES
[H][C@@]12CC[C@@](O)(C#C)[C@@]1(C)CC[C@@]1([H])[C@@]2([H])CCC2=CC3=C(C[C@]12C)C=NO3
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassLipids
ClassSteroids and Steroid Derivatives
SubclassAndrogens and Derivatives
Direct parentAndrogens and Derivatives
Alternative parentsHydroxysteroids; Ynones; Tertiary Alcohols; Isoxazoles; Cyclic Alcohols and Derivatives; Polyamines
Substituentsynone; cyclic alcohol; azole; isoxazole; tertiary alcohol; polyamine; alcohol; organonitrogen compound
Classification descriptionThis compound belongs to the androgens and derivatives. These are hydroxylated C19 steroid hormones. They are known to favour the development of masculine characteristics. They also show profound effects on scalp and body hair in humans.
Pharmacology
IndicationFor the treatment of endometriosis and fibrocystic breast disease (in patients unresponsive to simple measures). Also used for the prophylactic treatment of all types of hereditary angioedema in males and females.
PharmacodynamicsDanazol is a derivative of the synthetic steroid ethisterone, a modified testosterone. It was approved by the U.S. Food and Drug Administration (FDA) as the first drug to specifically treat endometriosis, but its role as a treatment for endometriosis has been largely replaced by the gonadotropin-releasing hormone (GnRH) agonists. Danazol has antigonadotropic and anti-estrogenic activities. Danazol acts as an anterior pituitary suppressant by inhibiting the pituitary output of gonadotropins. It possesses some androgenic properties.
Mechanism of actionAs a gonadotropin inhibitor, danazol suppresses the pituitary-ovarian axis possibly by inhibiting the output of pituitary gonadotropins. Danazol also depresses the preovulatory surge in output of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), thereby reducing ovarian estrogen production. Danazol may also directly inhibits ovarian steroidogenesis; bind to androgen, progesterone, and glucocorticoid receptors; bind to sex-hormone-binding globulin and corticosteroid-binding globulin; and increases the metabolic clearance rate of progesterone. Another mechanism of action by which danazol may use to facilitate regression of endometriosis is by decreasing IgG, IgM, and IgA concentrations, as well as phospholipid and IgG isotope autoantibodies. In the treatment of endometriosis, as a consequence of suppression of ovarian function, danazol causes both normal and ectopic endometrial tissues to become inactive and atrophic. This leads to anovulation and associated amenorrhea. In fibrocystic breast disease, the exact mechanism of action of danazol is unknown, but may be related to suppressed estrogenic stimulation as a result of decreased ovarian production of estrogen. A direct effect on steroid receptor sites in breast tissue is also possible. This leads to a disappearance of nodularity, relief of pain and tenderness, and possibly changes in the menstrual pattern. In terms of hereditary angioedema, danazol corrects the underlying biochemical deficiency by increasing serum concentrations of the deficient C1 esterase inhibitor, resulting in increased serum concentrations of the C4 component of the complement system. (Source: PharmGKB)
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingNot Available
Metabolism

Hepatic, to principal metabolites, ethisterone and 17-hydroxymethylethisterone.

SubstrateEnzymesProduct
Danazol
    17-hydroxymethylethisteroneDetails
    Danazol
      EthisteroneDetails
      Route of eliminationNot Available
      Half lifeApproximately 24 hours.
      ClearanceNot Available
      ToxicityNot Available
      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 + 0.9781
      Caco-2 permeable + 0.8866
      P-glycoprotein substrate Substrate 0.5938
      P-glycoprotein inhibitor I Non-inhibitor 0.5194
      P-glycoprotein inhibitor II Non-inhibitor 0.8893
      Renal organic cation transporter Non-inhibitor 0.8178
      CYP450 2C9 substrate Non-substrate 0.8487
      CYP450 2D6 substrate Non-substrate 0.9116
      CYP450 3A4 substrate Substrate 0.67
      CYP450 1A2 substrate Inhibitor 0.9107
      CYP450 2C9 substrate Non-inhibitor 0.7407
      CYP450 2D6 substrate Non-inhibitor 0.8731
      CYP450 2C19 substrate Inhibitor 0.5962
      CYP450 3A4 substrate Inhibitor 0.796
      CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.7692
      Ames test Non AMES toxic 0.6885
      Carcinogenicity Non-carcinogens 0.9083
      Biodegradation Not ready biodegradable 0.9562
      Rat acute toxicity 1.3291 LD50, mol/kg Not applicable
      hERG inhibition (predictor I) Weak inhibitor 0.6896
      hERG inhibition (predictor II) Non-inhibitor 0.8734
      Pharmacoeconomics
      Manufacturers
      • American therapeutics inc
      • Barr laboratories inc
      • Lannett holdings inc
      • Sanofi aventis us llc
      Packagers
      Dosage forms
      FormRouteStrength
      CapsuleOral
      Prices
      Unit descriptionCostUnit
      Danazol powder21.42USDg
      Danazol 200 mg capsule5.2USDcapsule
      Danocrine 200 mg capsule4.53USDcapsule
      Danazol 100 mg capsule2.92USDcapsule
      Cyclomen 200 mg Capsule2.31USDcapsule
      Danazol 50 mg capsule1.95USDcapsule
      Cyclomen 100 mg Capsule1.45USDcapsule
      Cyclomen 50 mg Capsule0.98USDcapsule
      DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
      PatentsNot Available
      Properties
      Statesolid
      Experimental Properties
      PropertyValueSource
      melting point225.6 °CPhysProp
      logP0.51PERRISSOUD,D & TESTA,B (1986)
      Predicted Properties
      PropertyValueSource
      water solubility1.76e-02 g/lALOGPS
      logP3.62ALOGPS
      logP3.46ChemAxon
      logS-4.3ALOGPS
      pKa (strongest acidic)17.59ChemAxon
      pKa (strongest basic)0.25ChemAxon
      physiological charge0ChemAxon
      hydrogen acceptor count2ChemAxon
      hydrogen donor count1ChemAxon
      polar surface area46.26ChemAxon
      rotatable bond count0ChemAxon
      refractivity98.54ChemAxon
      polarizability38.56ChemAxon
      number of rings5ChemAxon
      bioavailability1ChemAxon
      rule of fiveYesChemAxon
      Ghose filterYesChemAxon
      Veber's ruleNoChemAxon
      MDDR-like ruleNoChemAxon
      Spectra
      Spectra
      References
      Synthesis ReferenceNot Available
      General Reference
      1. Dmowski WP: Danazol. A synthetic steroid with diverse biologic effects. J Reprod Med. 1990 Jan;35(1 Suppl):69-74; discussion 74-5. Pubmed
      2. Donaldson VH: Danazol. Am J Med. 1989 Sep;87(3N):49N-55N. Pubmed
      3. Jenkin G: Review: The mechanism of action of danazol, a novel steroid derivative. Aust N Z J Obstet Gynaecol. 1980 May;20(2):113-8. Pubmed
      External Links
      ResourceLink
      KEGG DrugD00289
      PubChem Compound28417
      PubChem Substance46506475
      ChemSpider26436
      ChEBI4315
      ChEMBLCHEMBL1479
      Therapeutic Targets DatabaseDAP001017
      PharmGKBPA164749056
      Drug Product Database2018144
      RxListhttp://www.rxlist.com/cgi/generic/danazol.htm
      Drugs.comhttp://www.drugs.com/cdi/danazol.html
      WikipediaDanazol
      ATC CodesG03XA01
      AHFS Codes
      • 68:08.00
      PDB EntriesNot Available
      FDA labelNot Available
      MSDSshow(75 KB)
      Interactions
      Drug Interactions
      Drug
      AcenocoumarolThe androgen, danazol, may increase the anticoagulant effect of acenocoumarol.
      AnisindioneThe androgen, danazol, may increase the anticoagulant effect of anisindione.
      CarbamazepineDanazol may decrease the metabolism of carbamazepine. Monitor for changes in the therapeutic and adverse effects of carbamazepine if danazol is initiated, discontinued or dose changed.
      CyclosporineThe androgen, danazol, may increase the effect and toxicity of cyclosporine.
      DicoumarolThe androgen, danazol, may increase the anticoagulant effect of dicumarol.
      LovastatinRisk of severe myopathy/rhabdomyolysis with this combination
      TacrolimusDanazol may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Danazol therapy is initiated, discontinued or altered.
      WarfarinDanazol may increase the serum concentration and anticoagulant effect of warfarin. Monitor for changes in prothrombin time and therapeutic effects of warfarin if danazol is initiated, discontinued or dose changed.
      Food Interactions
      • Take without regard to meals.

      1. Estrogen receptor

      Kind: protein

      Organism: Human

      Pharmacological action: yes

      Actions: agonist

      Components

      Name UniProt ID Details
      Estrogen receptor P03372 Details

      References:

      1. Fujimoto J, Hori M, Itoh T, Ichigo S, Nishigaki M, Tamaya T: Danazol decreases transcription of estrogen receptor gene in human monocytes. Gen Pharmacol. 1995 May;26(3):507-16. Pubmed
      2. Snyder BW, Beecham GD, Winneker RC: Danazol suppression of luteinizing hormone in the rat: evidence for mediation by both androgen and estrogen receptors. Proc Soc Exp Biol Med. 1990 May;194(1):54-7. Pubmed
      3. Sanfilippo JS, Barrows GH, Apkarian RP, Wittliff JL: Evaluation of danazol influence upon the uterus using scanning electron microscopic morphometric and biochemical analyses. Surg Gynecol Obstet. 1985 May;160(5):421-8. Pubmed
      4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

      2. Androgen receptor

      Kind: protein

      Organism: Human

      Pharmacological action: yes

      Actions: agonist

      Components

      Name UniProt ID Details
      Androgen receptor P10275 Details

      References:

      1. Donaldson VH: Danazol. Am J Med. 1989 Sep;87(3N):49N-55N. Pubmed
      2. Sasagawa S, Shimizu Y, Kami H, Takeuchi T, Mita S, Imada K, Kato S, Mizuguchi K: Dienogest is a selective progesterone receptor agonist in transactivation analysis with potent oral endometrial activity due to its efficient pharmacokinetic profile. Steroids. 2008 Feb;73(2):222-31. Epub 2007 Oct 22. Pubmed
      3. Gomez F, Ruiz P, Lopez R, Rivera C, Romero S, Bernal JA: Effects of androgen treatment on expression of macrophage Fcgamma receptors. Clin Diagn Lab Immunol. 2000 Jul;7(4):682-6. Pubmed
      4. Roselli CE: The effect of anabolic-androgenic steroids on aromatase activity and androgen receptor binding in the rat preoptic area. Brain Res. 1998 May 11;792(2):271-6. Pubmed
      5. Dmowski WP: Danazol. A synthetic steroid with diverse biologic effects. J Reprod Med. 1990 Jan;35(1 Suppl):69-74; discussion 74-5. Pubmed

      3. Progesterone receptor

      Kind: protein

      Organism: Human

      Pharmacological action: yes

      Actions: agonist

      Components

      Name UniProt ID Details
      Progesterone receptor P06401 Details

      References:

      1. Beaumont H, Augood C, Duckitt K, Lethaby A: Danazol for heavy menstrual bleeding. Cochrane Database Syst Rev. 2007 Jul 18;(3):CD001017. Pubmed
      2. Sasagawa S, Shimizu Y, Kami H, Takeuchi T, Mita S, Imada K, Kato S, Mizuguchi K: Dienogest is a selective progesterone receptor agonist in transactivation analysis with potent oral endometrial activity due to its efficient pharmacokinetic profile. Steroids. 2008 Feb;73(2):222-31. Epub 2007 Oct 22. Pubmed
      3. Huang HF, Wang M: [Effects of gossypol acetate, danazol, progesterone and GnRH-A on estrogen and progesterone receptors of human endometrial cells] Zhongguo Zhong Xi Yi Jie He Za Zhi. 1994 Jun;14(6):352-3, 325. Pubmed
      4. Dmowski WP: Danazol. A synthetic steroid with diverse biologic effects. J Reprod Med. 1990 Jan;35(1 Suppl):69-74; discussion 74-5. Pubmed

      4. Gonadotropin-releasing hormone receptor

      Kind: protein

      Organism: Human

      Pharmacological action: yes

      Actions: negative modulator

      Components

      Name UniProt ID Details
      Gonadotropin-releasing hormone receptor P30968 Details

      References:

      1. Tian ZZ, Zhao H, Chen BY: [Effect of Chinese herbal medicine for nourishing yin and purging fire on mRNA expressions of gonadotropin-releasing hormone and its receptor in precocious puberty model rats] Zhongguo Zhong Xi Yi Jie He Za Zhi. 2003 Sep;23(9):695-8. Pubmed
      2. Menon M, Peegel H, Katta V: Inhibition of gonadotropin-releasing hormone receptors in rat anterior pituitary monolayer cell cultures by danazol. Am J Obstet Gynecol. 1986 Feb;154(2):367-72. Pubmed
      3. Roth C, Hegemann F, Hildebrandt J, Balzer I, Witt A, Wuttke W, Jarry H: Pituitary and gonadal effects of GnRH (gonadotropin releasing hormone) analogues in two peripubertal female rat models. Pediatr Res. 2004 Jan;55(1):126-33. Epub 2003 Nov 6. Pubmed
      4. Dmowski WP: Danazol. A synthetic steroid with diverse biologic effects. J Reprod Med. 1990 Jan;35(1 Suppl):69-74; discussion 74-5. Pubmed

      5. Putative gonadotropin-releasing hormone II receptor

      Kind: protein

      Organism: Human

      Pharmacological action: yes

      Actions: negative modulator

      Components

      Name UniProt ID Details
      Putative gonadotropin-releasing hormone II receptor Q96P88 Details

      References:

      1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
      2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
      3. Dmowski WP: Danazol. A synthetic steroid with diverse biologic effects. J Reprod Med. 1990 Jan;35(1 Suppl):69-74; discussion 74-5. Pubmed
      4. Menon M, Peegel H, Katta V: Inhibition of gonadotropin-releasing hormone receptors in rat anterior pituitary monolayer cell cultures by danazol. Am J Obstet Gynecol. 1986 Feb;154(2):367-72. Pubmed

      6. C-C motif chemokine 2

      Kind: protein

      Organism: Human

      Pharmacological action: unknown

      Actions: inhibitor

      Components

      Name UniProt ID Details
      C-C motif chemokine 2 P13500 Details

      References:

      1. Boucher A, Lemay A, Akoum A: Effect of hormonal agents on monocyte chemotactic protein-1 expression by endometrial epithelial cells of women with endometriosis. Fertil Steril. 2000 Nov;74(5):969-75. Pubmed
      2. Jolicoeur C, Lemay A, Akoum A: Comparative effect of danazol and a GnRH agonist on monocyte chemotactic protein-1 expression by endometriotic cells. Am J Reprod Immunol. 2001 Feb;45(2):86-93. Pubmed

      1. 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

      2. Cytochrome P450 3A4

      Kind: protein

      Organism: Human

      Pharmacological action: unknown

      Actions: inhibitor

      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

      1. Sex hormone-binding globulin

      Kind: protein

      Organism: Human

      Pharmacological action: yes

      Components

      Name UniProt ID Details
      Sex hormone-binding globulin P04278 Details

      References:

      1. De Leo V, Morgante G, La Marca A, Musacchio MC, Sorace M, Cavicchioli C, Petraglia F: A benefit-risk assessment of medical treatment for uterine leiomyomas. Drug Saf. 2002;25(11):759-79. Pubmed
      2. Telimaa S, Apter D, Reinila M, Ronnberg L, Kauppila A: Placebo-controlled comparison of hormonal and biochemical effects of danazol and high-dose medroxyprogesterone acetate. Eur J Obstet Gynecol Reprod Biol. 1990 Jul-Aug;36(1-2):97-105. Pubmed
      3. Donaldson VH: Danazol. Am J Med. 1989 Sep;87(3N):49N-55N. Pubmed
      4. Valimaki M, Nilsson CG, Roine R, Ylikorkala O: Comparison between the effects of nafarelin and danazol on serum lipids and lipoproteins in patients with endometriosis. J Clin Endocrinol Metab. 1989 Dec;69(6):1097-103. Pubmed
      5. Forbes KL, Dowsett M, Rose GL, Mudge JE, Jeffcoate SL: Dosage-related effects of danazol on sex hormone binding globulin and free and total androgen levels. Clin Endocrinol (Oxf). 1986 Nov;25(5):597-605. Pubmed

      Comments
      Drug created on July 13, 2007 14:36 / Updated on October 04, 2013 11:16