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Identification
NameClomifene
Accession NumberDB00882  (APRD00880)
TypeSmall Molecule
GroupsApproved, Investigational
Description

A triphenyl ethylene stilbene derivative which is an estrogen agonist or antagonist depending on the target tissue. [PubChem]

Structure
Thumb
Synonyms
SynonymLanguageCode
ClomifeneNot AvailableNot Available
ClomifenoSpanishINN
ClomifenumLatinINN
ClomipheneNot AvailableUSAN
Salts
Name/CAS Structure Properties
Clomifene citrate
Thumb
  • InChI Key: PYTMYKVIJXPNBD-OQKDUQJOSA-N
  • Monoisotopic Mass: 597.21294484
  • Average Mass: 598.083
DBSALT000490
Brand names
NameCompany
AndroxalNot Available
ClomidSanofi-Aventis
ClomifertNot Available
ClostilbegytEgis
OmifinSanofi
SeropheneAstraZeneca
Brand mixturesNot Available
Categories
CAS number911-45-5
WeightAverage: 405.96
Monoisotopic: 405.18594223
Chemical FormulaC26H28ClNO
InChI KeyGKIRPKYJQBWNGO-OCEACIFDSA-N
InChI
InChI=1S/C26H28ClNO/c1-3-28(4-2)19-20-29-24-17-15-22(16-18-24)25(21-11-7-5-8-12-21)26(27)23-13-9-6-10-14-23/h5-18H,3-4,19-20H2,1-2H3/b26-25+
IUPAC Name
{2-[4-(2-chloro-1,2-diphenylethenyl)phenoxy]ethyl}diethylamine
SMILES
CCN(CC)CCOC1=CC=C(C=C1)C(=C(Cl)C1=CC=CC=C1)C1=CC=CC=C1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassPhenylpropanoids and Polyketides
ClassStilbenes
SubclassNot Available
Direct parentStilbenes
Alternative parentsDiphenylmethanes; Phenylpropenes; Phenol Ethers; Alkyl Aryl Ethers; Tertiary Amines; Polyamines; Organochlorides
Substituentsphenylpropene; phenol ether; alkyl aryl ether; benzene; tertiary amine; polyamine; ether; organohalogen; organochloride; amine; organonitrogen compound
Classification descriptionThis compound belongs to the stilbenes. These are organic compounds containing a 1,2-diphenylethylene moiety. Stilbenes (C6-C2-C6 ) are derived from the common phenylpropene (C6-C3) skeleton building block. The introduction of one or more hydroxyl groups to a phenyl ring lead to stilbenoids.
Pharmacology
IndicationUsed mainly in female infertility due to anovulation (e.g. due to polycystic ovary syndrome) to induce ovulation.
PharmacodynamicsClomifene (previously clomiphene) is an orally administered, non steroidal, ovulatory stimulant that acts as a selective estrogen receptor modulator (SERM). Clomifene can lead to multiple ovulation, and hence increase the risk of conceiving twins. In comparison to purified FSH, the rate of ovarian hyperstimulation syndrome is low. There may be an increased risk of ovarian cancer and weight gain. Clomifene is capable of interacting with estrogen-receptor-containing tissues, including the hypothalamus, pituitary, ovary, endometrium, vagina, and cervix. It may compete with estrogen for estrogen-receptor-binding sites and may delay replenishment of intracellular estrogen receptors. Clomifene initiates a series of endocrine events culminating in a preovulatory gonadotropin surge and subsequent follicular rupture. The first endocrine event, in response to a course of clomifene therapy, is an increase in the release of pituitary gonadotropins. This initiates steroidogenesis and folliculogenesis resulting in growth of the ovarian follicle and an increase in the circulating level of estradiol. Following ovulation, plasma progesterone and estradiol rise and fall as they would in a normal ovulatory cycle.
Mechanism of actionClomifene has both estrogenic and anti-estrogenic properties, but its precise mechanism of action has not been determined. Clomifene appears to stumulate the release of gonadotropins, follicle-stimulating hormone (FSH), and leuteinizing hormone (LH), which leads to the development and maturation of ovarian follicle, ovulation, and subsequent development and function of the coprus luteum, thus resulting in pregnancy. Gonadotropin release may result from direct stimulation of the hypothalamic-pituitary axis or from a decreased inhibitory influence of estrogens on the hypothalamic-pituitary axis by competing with the endogenous estrogens of the uterus, pituitary, or hypothalamus. Clomifene has no apparent progestational, androgenic, or antrandrogenic effects and does not appear to interfere with pituitary-adrenal or pituitary-thyroid function.
AbsorptionBased on early studies with 14 C-labeled clomifene, the drug was shown to be readily absorbed orally in humans.
Volume of distributionNot Available
Protein bindingNot Available
Metabolism

Hepatic

Route of eliminationBased on early studies with 14C-labeled clomiphene citrate, the drug was shown to be readily absorbed orally in humans and excreted principally in the feces. Mean urinary excretion was approximately 8% with fecal excretion of about 42%.
Half life5-7 days
ClearanceNot Available
ToxicityThe acute oral LD50 of clomifene is 1700 mg/kg in mice and 5750 mg/kg in rats. The toxic dose in humans is not known. Toxic effects accompanying acute overdosage of clomifene have not been reported. Signs and symptoms of overdosage as a result of the use of more than the recommended dose during clomifene therapy include nausea, vomiting, vasomotor flushes, visual blurring, spots or flashes, scotomata, ovarian enlargement with pelvic or abdominal pain.
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 + 0.8723
Caco-2 permeable + 0.7235
P-glycoprotein substrate Substrate 0.7536
P-glycoprotein inhibitor I Inhibitor 0.7799
P-glycoprotein inhibitor II Non-inhibitor 0.6476
Renal organic cation transporter Inhibitor 0.7021
CYP450 2C9 substrate Non-substrate 0.7972
CYP450 2D6 substrate Non-substrate 0.6847
CYP450 3A4 substrate Substrate 0.7021
CYP450 1A2 substrate Inhibitor 0.9332
CYP450 2C9 substrate Non-inhibitor 0.6036
CYP450 2D6 substrate Inhibitor 0.8315
CYP450 2C19 substrate Inhibitor 0.7004
CYP450 3A4 substrate Non-inhibitor 0.8089
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.9254
Ames test Non AMES toxic 0.5
Carcinogenicity Non-carcinogens 0.621
Biodegradation Not ready biodegradable 0.9895
Rat acute toxicity 1.8805 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Strong inhibitor 0.8038
hERG inhibition (predictor II) Inhibitor 0.8672
Pharmacoeconomics
Manufacturers
  • Sanofi aventis us llc
  • Par pharmaceutical inc
  • Milex products inc
  • Emd serono inc
Packagers
Dosage forms
FormRouteStrength
TabletOral
Prices
Unit descriptionCostUnit
ClomiPHENE Citrate 30 50 mg tablet Box215.9USDbox
Clomiphene citrate powder47.74USDg
Clomid 50 mg tablet17.1USDtablet
Serophene 50 mg tablet11.08USDtablet
Clomiphene citrate 50 mg tab6.86USDtablet
Clomid 50 mg Tablet6.09USDtablet
Serophene 50 mg Tablet5.52USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point116.5-118Allen, R.E., Palopoli, F.P., Schumann, E.L. and Van Carnpen, M.G. Jr.; US. Patent 2,914,563; November 24, 1959; assigned to The Wrn. S. Merrell Company.
water solubilitySlightly solubleNot Available
logP7.2Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.000414ALOGPS
logP6.08ALOGPS
logP6.47ChemAxon
logS-6ALOGPS
pKa (Strongest Basic)9.31ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area12.47 Å2ChemAxon
Rotatable Bond Count9ChemAxon
Refractivity133.76 m3·mol-1ChemAxon
Polarizability46.7 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Allen, R.E., Palopoli, F.P., Schumann, E.L. and Van Carnpen, M.G. Jr.; US. Patent 2,914,563; November 24, 1959; assigned to The Wrn. S. Merrell Company.

General Reference
  1. Purvin VA: Visual disturbance secondary to clomiphene citrate. Arch Ophthalmol. 1995 Apr;113(4):482-4. Pubmed
  2. Hayon T, Atlas L, Levy E, Dvilansky A, Shpilberg O, Nathan I: Multifactorial activities of nonsteroidal antiestrogens against leukemia. Cancer Detect Prev. 2003;27(5):389-96. Pubmed
  3. Fritz MA, Holmes RT, Keenan EJ: Effect of clomiphene citrate treatment on endometrial estrogen and progesterone receptor induction in women. Am J Obstet Gynecol. 1991 Jul;165(1):177-85. Pubmed
  4. Hughes E, Brown J, Collins JJ, Vanderkerchove P: Clomiphene citrate for unexplained subfertility in women. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD000057. Pubmed
  5. Brown J, Farquhar C, Beck J, Boothroyd C, Hughes E: Clomiphene and anti-oestrogens for ovulation induction in PCOS. Cochrane Database Syst Rev. 2009 Oct 7;(4):CD002249. Pubmed
  6. Use of clomiphene citrate in women. Fertil Steril. 2006 Nov;86(5 Suppl 1):S187-93. Pubmed
  7. Homburg R: Oral agents for ovulation induction—clomiphene citrate versus aromatase inhibitors. Hum Fertil (Camb). 2008 Mar;11(1):17-22. Pubmed
  8. Homburg R: Clomiphene citrate—end of an era? A mini-review. Hum Reprod. 2005 Aug;20(8):2043-51. Epub 2005 May 5. Pubmed
External Links
ResourceLink
KEGG DrugD00962
KEGG CompoundC06917
BindingDB50170640
ChEBI3752
ChEMBLCHEMBL1200667
Therapeutic Targets DatabaseDAP001013
PharmGKBPA449046
Drug Product Database640158
RxListhttp://www.rxlist.com/cgi/generic/clomiph.htm
PDRhealthhttp://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/clo1088.shtml
WikipediaClomifene
ATC CodesG03GB02
AHFS Codes
  • 68:16.12
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Interactions
Drug Interactions
Drug
AmobarbitalThe enzyme inducer, amobarbital, decreases the effect of the hormone agent, clomifene.
AprobarbitalThe enzyme inducer, aprobarbital, decreases the effect of the hormone agent, clomifene.
ButabarbitalThe enzyme inducer, butabarbital, decreases the effect of the hormone agent, clomifene.
ButalbitalThe enzyme inducer, butalbital, decreases the effect of the hormone agent, clomifene.
ButethalThe enzyme inducer, butethal, decreases the effect of the hormone agent, clomifene.
EthotoinThe enzyme inducer, ethotoin, decreases the effect of the hormone agent, clomifene.
FosphenytoinThe enzyme inducer, fosphenytoin, decreases the effect of the hormone agent, clomifene.
GriseofulvinThe enzyme inducer, griseofulvin, decreases the effect of the hormone agent, clomifene.
HeptabarbitalThe enzyme inducer, heptabarbital, decreases the effect of the hormone agent, clomifene.
HexobarbitalThe enzyme inducer, hexobarbital, decreases the effect of the hormone agent, clomifene.
MephenytoinThe enzyme inducer, mephenytoin, decreases the effect of the hormone agent, clomifene.
MethohexitalThe enzyme inducer, methohexital, decreases the effect of the hormone agent, clomifene.
MethylphenobarbitalThe enzyme inducer, methylphenobarbital, decreases the effect of the hormone agent, clomifene.
PentobarbitalThe enzyme inducer, pentobarbital, decreases the effect of the hormone agent, clomifene.
PhenobarbitalThe enzyme inducer, phenobarbital, decreases the effect of the hormone agent, clomifene.
PhenytoinThe enzyme inducer, phenytoin, decreases the effect of the hormone agent, clomifene.
PrednisoloneThe estrogenic agent, clomifene, may increase the effect of the corticosteroid, prednisolone.
PrednisoneThe estrogenic agent, clomifene, may increase the effect of corticosteroid, prednisone.
PrimidoneThe enzyme inducer, primidone, decreases the effect of the hormone agent, clomifene.
RaloxifeneAssociation not recommended
SecobarbitalThe enzyme inducer, secobarbital, decreases the effect of the hormone agent, clomifene.
TalbutalThe enzyme inducer, talbutal, decreases the effect of the hormone agent, clomifene.
Ursodeoxycholic acidEstrogens decreases the effect of ursodiol
Food Interactions
  • Take without regard to meals.

Targets

1. Estrogen receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist agonist

Components

Name UniProt ID Details
Estrogen receptor P03372 Details

References:

  1. Sasson S: Equilibrium binding analysis of estrogen agonists and antagonists: relation to the activation of the estrogen receptor. Pathol Biol (Paris). 1991 Jan;39(1):59-69. Pubmed
  2. Kurosawa T, Hiroi H, Momoeda M, Inoue S, Taketani Y: Clomiphene citrate elicits estrogen agonistic/antagonistic effects differentially via estrogen receptors alpha and beta. Endocr J. 2010;57(6):517-21. Epub 2010 Apr 6. Pubmed
  3. Hughes E, Brown J, Collins JJ, Vanderkerchove P: Clomiphene citrate for unexplained subfertility in women. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD000057. Pubmed
  4. Brown J, Farquhar C, Beck J, Boothroyd C, Hughes E: Clomiphene and anti-oestrogens for ovulation induction in PCOS. Cochrane Database Syst Rev. 2009 Oct 7;(4):CD002249. Pubmed
  5. Use of clomiphene citrate in women. Fertil Steril. 2006 Nov;86(5 Suppl 1):S187-93. Pubmed
  6. Overbeek A, Lambalk N: Pharmacogenomics of ovulation induction: facilitating decisions on who, when and how to treat. Pharmacogenomics. 2009 Sep;10(9):1377-9. Pubmed
  7. Homburg R: Oral agents for ovulation induction—clomiphene citrate versus aromatase inhibitors. Hum Fertil (Camb). 2008 Mar;11(1):17-22. Pubmed
  8. Homburg R: Clomiphene citrate—end of an era? A mini-review. Hum Reprod. 2005 Aug;20(8):2043-51. Epub 2005 May 5. Pubmed
  9. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

Enzymes

1. Cholesterol side-chain cleavage enzyme, mitochondrial

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cholesterol side-chain cleavage enzyme, mitochondrial P05108 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

3. Cytochrome P450 1A1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inducer

Components

Name UniProt ID Details
Cytochrome P450 1A1 P04798 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

4. Cytochrome P450 1A2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 1A2 P05177 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

5. Cytochrome P450 2A6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2A6 P11509 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

6. Cytochrome P450 2E1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2E1 P05181 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

7. 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

Transporters

1. Multidrug resistance protein 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Multidrug resistance protein 1 P08183 Details

References:

  1. Rao US, Fine RL, Scarborough GA: Antiestrogens and steroid hormones: substrates of the human P-glycoprotein. Biochem Pharmacol. 1994 Jul 19;48(2):287-92. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on April 07, 2014 15:22