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Identification
NameRaloxifene
Accession NumberDB00481  (APRD00400)
Typesmall molecule
Groupsapproved, investigational
Description

A second generation selective estrogen receptor modulator (SERM) used to prevent osteoporosis in postmenopausal women. It has estrogen agonist effects on bone and cholesterol metabolism but behaves as a complete estrogen antagonist on mammary gland and uterine tissue. [PubChem]

Structure
Thumb
Synonyms
SynonymLanguageCode
RALNot AvailableNot Available
RaloxifenoSpanishINN
RaloxifenumLatinINN
Salts
Name/CAS Structure Properties
Raloxifene Hydrochloride
82640-04-8
Thumb
  • InChI Key: BKXVVCILCIUCLG-UHFFFAOYSA-N
  • Monoisotopic Mass: 509.142756786
  • Average Mass: 510.044
DBSALT000272
Brand names
NameCompany
EvistaNot Available
KeoxifeneNot Available
Brand mixturesNot Available
Categories
CAS number84449-90-1
WeightAverage: 473.583
Monoisotopic: 473.166079047
Chemical FormulaC28H27NO4S
InChI KeyGZUITABIAKMVPG-UHFFFAOYSA-N
InChI
InChI=1S/C28H27NO4S/c30-21-8-4-20(5-9-21)28-26(24-13-10-22(31)18-25(24)34-28)27(32)19-6-11-23(12-7-19)33-17-16-29-14-2-1-3-15-29/h4-13,18,30-31H,1-3,14-17H2
IUPAC Name
2-(4-hydroxyphenyl)-3-({4-[2-(piperidin-1-yl)ethoxy]phenyl}carbonyl)-1-benzothiophen-6-ol
SMILES
OC1=CC=C(C=C1)C1=C(C(=O)C2=CC=C(OCCN3CCCCC3)C=C2)C2=C(S1)C=C(O)C=C2
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassPhenylpropanoids and Polyketides
ClassStilbenes
SubclassNot Available
Direct parentStilbenes
Alternative parentsAcetophenones; Benzothiophenes; Thiophene Carboxylic Acids and Derivatives; Phenol Ethers; Benzoyl Derivatives; Phenols and Derivatives; Alkyl Aryl Ethers; Piperidines; Tertiary Amines; Ketones; Enolates; Polyamines; Enols
Substituentsacetophenone; benzothiophene; benzoyl; thiophene carboxylic acid or derivative; phenol ether; phenol derivative; alkyl aryl ether; piperidine; benzene; thiophene; ketone; tertiary amine; polyamine; ether; enolate; enol; amine; carbonyl group; 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
IndicationFor the prevention and treatment of osteoporosis in post-menopausal women, as well as prevention and treatment of corticosteroid-induced bone loss. Also for the reduction in the incidence of invasive breast cancer in postmenopausal women with osteoporosis or have a high risk for developing breast cancer.
PharmacodynamicsRaloxifene, a selective estrogen receptor modulator (SERM) of the benzothiophene class, is similar to tamoxifen in that it produces estrogen-like effects on bone and lipid metabolism, while antagonizing the effects of estrogen on breast and uterine tissue. Raloxifene differs chemically and pharmacologically from naturally occuring estrogens, synthetic steroidal and nonsteroidal compounds with estrogenic activity, and antiestrogens. Estrogens play an important role in the reproductive, skeletal, cardiovascular, and central nervous systems in women, and act principally by regulating gene expression. When estrogen binds to a ligand-binding domain of the estrogen receptor, biologic response is initiated as a result of a conformational change of the estrogen receptor, which leads to gene transcription through specific estrogen response elements of target gene promoters. The subsequent activation or repression of the target gene is mediated through 2 distinct transactivation domains of the receptor: AF-1 and AF-2. The estrogen receptor also mediates gene transcription using different response elements and other signalling pathways. The role of estrogen as a regulator of bone mass is well established. In postmenopausal women, the progressive loss of bone mass is related to decreased ovarian function and a reduction in the level of circulation estrogens. Estrogen also has favourable effects on blood cholesterol.
Mechanism of actionRaloxifene binds to estrogen receptors, resulting in differential expression of multiple estrogen-regulated genes in different tissues. Raloxifene produces estrogen-like effects on bone, reducing resorption of bone and increasing bone mineral density in postmenopausal women, thus slowing the rate of bone loss. The maintenance of bone mass by raloxifene and estrogens is, in part, through the regulation of the gene-encoding transforming growth factor-β3 (TGF-β3), which is a bone matrix protein with antiosteoclastic properties. Raloxifene activates TGF-β3 through pathways that are estrogen receptor-mediated but involve DNA sequences distinct from the estrogen response element. The drug also binds to the estrogen receptor and acts as an estrogen agonist in preosteoclastic cells, which results in the inhibtion of their proliferative capacity. This inhibition is thought to contribute to the drug's effect on bone resorption. Other mechanisms include the suppression of activity of the bone-resorbing cytokine interleukin-6 promoter activity. Raloxifene also antagonizes the effects of estrogen on mammary tissue and blocks uterotrophic responses to estrogen. By competing with estrogens for the estrogen receptors in reproductive tissue, raloxifene prevents the transcriptional activation of genes containing the estrogen response element. As well, raloxifene inhibits the estradiol-dependent proliferation of MCF-7 human mammary tumor cells in vitro. The mechansim of action of raloxifene has not been fully determined, but evidence suggests that the drug's tissue-specific estrogen agonist or antagonist activity is related to the structural differences between the raloxifene-estrogen receptor complex (specifically the surface topography of AF-2) and the estrogen-estrogen receptor complex. Also, the existence of at least 2 estrogen receptors (ERα, ERβ) may contribute to the tissue specificity of raloxifene.
AbsorptionApproximately 60% of an oral dose is absorbed, but presystemic glucuronide conjugation is extensive. Absolute bioavailability of raloxifene is 2.0%
Volume of distribution
  • 2348 L/kg [oral administration of single doses ranging from 30 to 150 mg]
Protein binding95%
Metabolism

Hepatic, raloxifene undergoes extensive first-pass metabolism to the glucuronide conjugates: raloxifene-4'-glucuronide, raloxifene-6-glucuronide, and raloxifene-6, 4'-diglucuronide. No other metabolites have been detected, providing strong evidence that raloxifene is not metabolized by cytochrome P450 pathways

Route of eliminationRaloxifene is primarily excreted in feces, and less than 0.2% is excreted unchanged in urine.
Half life27.7
Clearance
  • 44.1 L/kg•hr [Healthy Postmenopausal Woman with Single Dose]
  • 47.4 L/kg•hr [Healthy Postmenopausal Woman with Multiple Dose]
  • Oral cl=44.1 L/kg•hr
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 + 0.9865
Blood Brain Barrier + 0.8661
Caco-2 permeable - 0.8957
P-glycoprotein substrate Substrate 0.7751
P-glycoprotein inhibitor I Non-inhibitor 0.6231
P-glycoprotein inhibitor II Inhibitor 0.9366
Renal organic cation transporter Inhibitor 0.634
CYP450 2C9 substrate Non-substrate 0.7897
CYP450 2D6 substrate Non-substrate 0.9116
CYP450 3A4 substrate Substrate 0.5198
CYP450 1A2 substrate Non-inhibitor 0.9045
CYP450 2C9 substrate Non-inhibitor 0.9071
CYP450 2D6 substrate Inhibitor 0.8932
CYP450 2C19 substrate Inhibitor 0.8986
CYP450 3A4 substrate Inhibitor 0.7617
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.8222
Ames test Non AMES toxic 0.8487
Carcinogenicity Non-carcinogens 0.9433
Biodegradation Not ready biodegradable 0.9587
Rat acute toxicity 2.5287 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.6322
hERG inhibition (predictor II) Inhibitor 0.5779
Pharmacoeconomics
Manufacturers
  • Eli lilly and co
Packagers
Dosage forms
FormRouteStrength
TabletOral
Prices
Unit descriptionCostUnit
Evista 60 mg tablet4.37USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States64588111997-03-102017-03-10
United States53937631995-07-282012-07-28
Canada21584002006-10-242015-09-15
Canada21013561998-11-172013-07-27
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point143-147 °CNot Available
water solubility0.25mg/LNot Available
logP5.2Not Available
Predicted Properties
PropertyValueSource
water solubility5.12e-04 g/lALOGPS
logP5.45ALOGPS
logP5.69ChemAxon
logS-6ALOGPS
pKa (strongest acidic)8.89ChemAxon
pKa (strongest basic)7.95ChemAxon
physiological charge1ChemAxon
hydrogen acceptor count5ChemAxon
hydrogen donor count2ChemAxon
polar surface area70ChemAxon
rotatable bond count7ChemAxon
refractivity135.48ChemAxon
polarizability52.55ChemAxon
number of rings5ChemAxon
bioavailability1ChemAxon
rule of fiveNoChemAxon
Ghose filterNoChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleYesChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Massimo Ferrari, Fabrizio Zinetti, Paolo Belotti, “Process for preparing raloxifene hydrochloride.” U.S. Patent US20070100147, issued May 03, 2007.

US20070100147
General Reference
  1. : A STARring role for raloxifene? Lancet Oncol. 2006 Jun;7(6):443. Pubmed
  2. Heringa M: Review on raloxifene: profile of a selective estrogen receptor modulator. Int J Clin Pharmacol Ther. 2003 Aug;41(8):331-45. Pubmed
  3. Barrett-Connor E: Raloxifene: risks and benefits. Ann N Y Acad Sci. 2001 Dec;949:295-303. Pubmed
  4. Khovidhunkit W, Shoback DM: Clinical effects of raloxifene hydrochloride in women. Ann Intern Med. 1999 Mar 2;130(5):431-9. Pubmed
  5. Cummings SR, Eckert S, Krueger KA, Grady D, Powles TJ, Cauley JA, Norton L, Nickelsen T, Bjarnason NH, Morrow M, Lippman ME, Black D, Glusman JE, Costa A, Jordan VC: The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. JAMA. 1999 Jun 16;281(23):2189-97. Pubmed
  6. Bryant HU, Glasebrook AL, Yang NN, Sato M: An estrogen receptor basis for raloxifene action in bone. J Steroid Biochem Mol Biol. 1999 Apr-Jun;69(1-6):37-44. Pubmed
  7. Balfour JA, Goa KL: Raloxifene. Drugs Aging. 1998 Apr;12(4):335-41; discussion 342. Pubmed
  8. Clemett D, Spencer CM: Raloxifene: a review of its use in postmenopausal osteoporosis. Drugs. 2000 Aug;60(2):379-411. Pubmed
  9. Silverman SL: New selective estrogen receptor modulators (SERMs) in development. Curr Osteoporos Rep. 2010 Sep;8(3):151-3. Pubmed
  10. Diez-Perez A: Selective estrogen receptor modulators (SERMS). Arq Bras Endocrinol Metabol. 2006 Aug;50(4):720-34. Pubmed
External Links
ResourceLink
KEGG CompoundC07228
PubChem Compound5035
PubChem Substance46506514
ChemSpider4859
BindingDB19441
ChEBI8772
ChEMBLCHEMBL81
Therapeutic Targets DatabaseDAP000792
PharmGKBPA451221
IUPHAR2820
Guide to Pharmacology2820
HETRAL
Drug Product Database2239028
RxListhttp://www.rxlist.com/cgi/generic/raloxif.htm
Drugs.comhttp://www.drugs.com/cdi/raloxifene.html
PDRhealthhttp://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/evi1169.shtml
WikipediaRaloxifene
ATC CodesG03XC01
AHFS Codes
  • 68:16.12
PDB EntriesNot Available
FDA labelshow(2.11 MB)
MSDSshow(57 KB)
Interactions
Drug Interactions
Drug
ChlorotrianiseneAssociation not recommended
CholestyramineThe resin decreases the effect of raloxifene
ClomifeneAssociation not recommended
ColesevelamBile Acid Sequestrants may decrease the absorption of Raloxifene. It would seem prudent to separate the doses of raloxifene and bile acid sequestrants by at least 2 hours. The manufacturer of raloxifene recommends against coadministration of these agents.1 The manufacturer of colesevelam recommends that drugs should be administered at least 1 hour before or 4 hours after colesevelam.
ColestipolThe resin decreases the effect of raloxifene
Conjugated EstrogensAssociation not recommended
DiethylstilbestrolAssociation not recommended
EstradiolAssociation not recommended
EstriolAssociation not recommended
EstropipateAssociation not recommended
Ethinyl EstradiolAssociation not recommended
LevothyroxineRaloxifene decreases absorption of levothyroxine
MestranolAssociation not recommended
Food Interactions
  • Avoid alcohol.
  • Take without regard to meals.

Targets

1. Estrogen receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: agonist

Components

Name UniProt ID Details
Estrogen receptor P03372 Details

References:

  1. Khovidhunkit W, Shoback DM: Clinical effects of raloxifene hydrochloride in women. Ann Intern Med. 1999 Mar 2;130(5):431-9. Pubmed
  2. Cummings SR, Eckert S, Krueger KA, Grady D, Powles TJ, Cauley JA, Norton L, Nickelsen T, Bjarnason NH, Morrow M, Lippman ME, Black D, Glusman JE, Costa A, Jordan VC: The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. JAMA. 1999 Jun 16;281(23):2189-97. Pubmed
  3. Bryant HU, Glasebrook AL, Yang NN, Sato M: An estrogen receptor basis for raloxifene action in bone. J Steroid Biochem Mol Biol. 1999 Apr-Jun;69(1-6):37-44. Pubmed
  4. Figtree GA, Lu Y, Webb CM, Collins P: Raloxifene acutely relaxes rabbit coronary arteries in vitro by an estrogen receptor-dependent and nitric oxide-dependent mechanism. Circulation. 1999 Sep 7;100(10):1095-101. Pubmed
  5. Schafer JI, Liu H, Tonetti DA, Jordan VC: The interaction of raloxifene and the active metabolite of the antiestrogen EM-800 (SC 5705) with the human estrogen receptor. Cancer Res. 1999 Sep 1;59(17):4308-13. Pubmed
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  7. Scott JA, Da Camara CC, Early JE: Raloxifene: a selective estrogen receptor modulator. Am Fam Physician. 1999 Sep 15;60(4):1131-9. Pubmed
  8. Matsumoto T: [Selective estrogen receptor modulators (SERMs)] Clin Calcium. 2006 Sep;16(9):1520-25. Pubmed
  9. Moen MD, Keating GM: Raloxifene: a review of its use in the prevention of invasive breast cancer. Drugs. 2008;68(14):2059-83. Pubmed

2. Estrogen receptor beta

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: agonist

Components

Name UniProt ID Details
Estrogen receptor beta Q92731 Details

References:

  1. Bryant HU, Glasebrook AL, Yang NN, Sato M: An estrogen receptor basis for raloxifene action in bone. J Steroid Biochem Mol Biol. 1999 Apr-Jun;69(1-6):37-44. Pubmed
  2. Iannone MA, Consler TG, Pearce KH, Stimmel JB, Parks DJ, Gray JG: Multiplexed molecular interactions of nuclear receptors using fluorescent microspheres. Cytometry. 2001 Aug 1;44(4):326-37. Pubmed
  3. Zhou W, Koldzic-Zivanovic N, Clarke CH, de Beun R, Wassermann K, Bury PS, Cunningham KA, Thomas ML: Selective estrogen receptor modulator effects in the rat brain. Neuroendocrinology. 2002 Jan;75(1):24-33. Pubmed
  4. Sun J, Huang YR, Harrington WR, Sheng S, Katzenellenbogen JA, Katzenellenbogen BS: Antagonists selective for estrogen receptor alpha. Endocrinology. 2002 Mar;143(3):941-7. Pubmed
  5. Kim IY, Seong DH, Kim BC, Lee DK, Remaley AT, Leach F, Morton RA, Kim SJ: Raloxifene, a selective estrogen receptor modulator, induces apoptosis in androgen-responsive human prostate cancer cell line LNCaP through an androgen-independent pathway. Cancer Res. 2002 Jul 1;62(13):3649-53. Pubmed
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

Enzymes

1. Cytochrome P450 2B6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2B6 P20813 Details

References:

  1. Walsky RL, Astuccio AV, Obach RS: Evaluation of 227 drugs for in vitro inhibition of cytochrome P450 2B6. J Clin Pharmacol. 2006 Dec;46(12):1426-38. Pubmed

2. Cytochrome P450 2C8

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2C8 P10632 Details

References:

  1. Walsky RL, Gaman EA, Obach RS: Examination of 209 drugs for inhibition of cytochrome P450 2C8. J Clin Pharmacol. 2005 Jan;45(1):68-78. Pubmed
  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. Aldehyde oxidase

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Aldehyde oxidase Q06278 Details

References:

  1. Obach RS: Potent inhibition of human liver aldehyde oxidase by raloxifene. Drug Metab Dispos. 2004 Jan;32(1):89-97. Pubmed
  2. Obach RS, Huynh P, Allen MC, Beedham C: Human liver aldehyde oxidase: inhibition by 239 drugs. J Clin Pharmacol. 2004 Jan;44(1):7-19. Pubmed
  3. Sahi J, Khan KK, Black CB: Aldehyde oxidase activity and inhibition in hepatocytes and cytosolic fractions from mouse, rat, monkey and human. Drug Metab Lett. 2008 Aug;2(3):176-83. Pubmed

4. 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

5. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate 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

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:10