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Identification
Name Clomifene
Accession Number DB00882 (APRD00880)
Type small molecule
Groups approved
Description

A triphenyl ethylene stilbene derivative which is an estrogen agonist or antagonist depending on the target tissue. [PubChem]
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • Chlomaphene
  • Chloramifene
  • Chloramiphene
  • Cisclomiphene
  • Clomifene citrate
  • Clomifeno
  • clomiphene
  • Clomiphene Citrate
  • Clomiphene citrate (Z,E)
  • Clomiphene dihydrogen citrate
  • Racemic clomiphene citrate
  • Zuclomiphene citrate
Brand names
  • Androxal
  • Clomid
  • Clomifert
  • Clomiphene
  • Clomiphene B
  • Clomivid
  • Clomphid
  • Clostilbegyt
  • Dyneric
  • Genozym
  • Ikaclomin
  • Milophene
  • Omifin
  • Serophene
Brand name mixtures Not Available
Categories
  • Selective Estrogen Receptor Modulators
  • Estrogen Antagonists
  • Fertility Agents, Female
CAS number 911-45-5
Weight Average: 405.96
Monoisotopic: 405.185942230
Chemical Formula C26H28ClNO
InChI Key InChIKey=GKIRPKYJQBWNGO-QPLCGJKRSA-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-
Plain Text
IUPAC Name
(2-{4-[(Z)-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
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Stilbenes
Substructures
  • Stilbenes
  • Alkanes and Alkenes
  • Phenols and Derivatives
  • Phenylpropenes
  • Ethers
  • Halogen Derivatives
  • Benzene and Derivatives
  • Aliphatic and Aryl Amines
  • Isoprenes
  • Aromatic compounds
  • Anisoles
  • Styrene Derivatives
  • Phenyl Esters
Pharmacology
Indication Used mainly in female infertility due to anovulation (e.g. due to polycystic ovary syndrome) to induce ovulation.
Pharmacodynamics Clomifene (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 action Clomifene 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.
Absorption Based on early studies with 14 C-labeled clomifene, the drug was shown to be readily absorbed orally in humans.
Volume of distribution Not Available
Protein binding Not Available
Metabolism

Hepatic
Route of elimination Based 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 life 5-7 days
Clearance Not Available
Toxicity The 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
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Sanofi aventis us llc
  • Par pharmaceutical inc
  • Milex products inc
  • Emd serono inc
Packagers
Dosage forms
Form Route Strength
Tablet Oral
Prices
Unit description Cost Unit
ClomiPHENE Citrate 30 50 mg tablet Box 215.9 USD box
Clomiphene citrate powder 47.74 USD g
Clomid 50 mg tablet 17.1 USD tablet
Serophene 50 mg tablet 11.08 USD tablet
Clomiphene citrate 50 mg tab 6.86 USD tablet
Clomid 50 mg Tablet 6.09 USD tablet
Serophene 50 mg Tablet 5.52 USD tablet
Patents Not Available
Properties
State solid
Melting point Not Available
Experimental Properties
Property Value Source
water solubility Slightly soluble PhysProp
logP 7.2 PhysProp
Predicted Properties
Property Value Source
water solubility 4.14e-04 g/l ALOGPS
logP 6.08 ALOGPS
logP 6.47 ChemAxon Molconvert
logS -5.99 ALOGPS
pKa ChemAxon Molconvert
hydrogen acceptor count 2 ChemAxon Molconvert
hydrogen donor count 0 ChemAxon Molconvert
polar surface area 12.47 ChemAxon Molconvert
rotatable bond count 9 ChemAxon Molconvert
refractivity 133.76 ChemAxon Molconvert
polarizability 46.74 ChemAxon Molconvert
References
Synthesis Reference Not Available
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
Resource Link
KEGG Drug D00962 Link_out
PubChem Compound 1548955 Link_out
PubChem Substance 46504463 Link_out
ChemSpider 1265969 Link_out
BindingDB 50170640 Link_out
ChEBI 3752 Link_out
ChEMBL 3752 Link_out
Therapeutic Targets Database DAP001013 Link_out
PharmGKB PA449047 Link_out
Drug Product Database 640158 Link_out
RxList http://www.rxlist.com/cgi/generic/clomiph.htm Link_out
PDRhealth http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/clo1088.shtml Link_out
Wikipedia http://en.wikipedia.org/wiki/Clomifene Link_out
ATC Codes
  • G03GB02
AHFS Codes
  • 68:16.12
PDB Entries Not Available
FDA label Not Available
MSDS Not Available
Interactions
Drug Interactions Not Available
Food Interactions
  • Take without regard to meals.
Targets

1. Estrogen receptor

Pharmacological action: yes
Actions: antagonist, agonist

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. 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

Actions: inhibitor

Catalyzes the side-chain cleavage reaction of cholesterol to pregnenolone

UniProt ID: P05108 Link_out
Gene: CYP11A1 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

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

3. Cytochrome P450 1A1

Actions: inducer

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics

UniProt ID: P04798 Link_out
Gene: CYP1A1 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

4. Cytochrome P450 1A2

Actions: inhibitor

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N3-demethylation. Also acts in the metabolism of aflatoxin B1 and acetaminophen

UniProt ID: P05177 Link_out
Gene: CYP1A2
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

5. Cytochrome P450 2A6

Actions: inhibitor

Exhibits a high coumarin 7-hydroxylase activity. Can act in the hydroxylation of the anti-cancer drugs cyclophosphamide and ifosphamide. Competent in the metabolic activation of aflatoxin B1. Constitutes the major nicotine C-oxidase

UniProt ID: P11509 Link_out
Gene: CYP2A6
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

6. Cytochrome P450 2E1

Actions: inhibitor

Metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic or carcinogenic forms

UniProt ID: P05181 Link_out
Gene: CYP2E1 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

7. Cytochrome P450 3A4

Actions: inhibitor

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
Transporters

1. Multidrug resistance protein 1

Actions: substrate

Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells

UniProt ID: P08183 Link_out
Gene: ABCB1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Comments
Drug created on June 13, 2005 07:24 / Updated on April 19, 2011 15:07

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.