Raloxifene

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Identification

Summary

Raloxifene is a selective estrogen receptor modulator that is used to prevent and treat osteoporosis and reduce the risk of invasive breast cancer in high-risk postmenopausal women.

Brand Names

Evista, Optruma

Generic Name

Raloxifene

DrugBank Accession Number

DB00481

Background

Raloxifene is a second generation selective estrogen receptor modulator (SERM) that mediates anti-estrogenic effects on breast and uterine tissues, and estrogenic effects on bone, lipid metabolism, and blood coagulation.^6,12 Exhibiting tissue-specific effects distinct from estradiol, raloxifene is the first of the benzothiophene group of antiestrogens to be labelled a SERM.⁷ Available in many countries worldwide, raloxifene was initially approved by the FDA in December, 1997 under the market name Evista® for the management and prevention of osteoporosis in postmenopausal women and reduction in risk for invasive breast cancer in postmenopausal women with osteoporosis or those who are at high risk for invasive breast cancer. However, it has a negligible effect on altering the development and progression of breast cancer itself.^Label The most common causes of osteoporosis include postmenopausal deficiency of estrogen and age-related deterioration in bone homeostasis. Due to the risk of bone fractures that may lead to morbidities and reduced quality of life, the management of osteoporosis in postmenopausal women with the use of therapeutic agents in addition to concurrent therapies is critical. Due to the decline in estrogen levels in postmenopausal osteoporosis, hormone replacement therapy (HRT), such as estradiol, has been used to ameliorate the condition. However, due to the off-target actions by HRT, newer non-hormonal agents such as raloxifene and tamoxifen have been developed to reduce adverse events through selective pharmacological actions on tissue-specific therapeutic targets.¹²

The main effects of raloxifene are to preserve the bone mineral density and decrease the risk of breast cancer in postmenopausal women. Compared to estrogen and tamoxifen, raloxifene was not associated with an increased risk of uterine cancer and it does not cause endometrial proliferation.¹ Although rare, there was an increased risk of venous thromboembolism during clinical trials of postmenopausal women receiving raloxifene. In addition, a clinical study consisting of postmenopausal women with documented coronary heart disease or at increased risk for coronary events showed an increased risk for fatal stroke with raloxifene therapy compared to placebo.^Label It is strongly advised that the risk-benefit ratio is considered before starting raloxifene therapy in women at risk of thromboembolic disease or strokes, such as the prior history of stroke, transient ischemic attack, atrial fibrillation, hypertension, or cigarette smoking.^Label

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Raloxifene (DB00481)

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Weight

Average: 473.583
Monoisotopic: 473.166079047

Chemical Formula

C₂₈H₂₇NO₄S

Synonyms

• (2-(4-Hydroxyphenyl)-6-hydroxybenzo(b)thien-3-yl)(4-(2-(1-piperidinyl)ethoxy)phenyl)methanone
• Raloxifène
• Raloxifene
• Raloxifeno
• Raloxifenum

External IDs

• J22.982B
• LY 139481
• LY-139481

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Pharmacology

Indication

Indicated for the prevention and treatment of osteoporosis in postmenopausal women, as well as prevention and treatment of corticosteroid-induced bone loss.^Label

Indicated for the reduction in the risk of invasive breast cancer in postmenopausal women with osteoporosis or postmenopausal women with a high risk for invasive breast cancer.^Label

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Prevention of	Invasive breast cancer		••••••••••••	••••••••••••••	•••• •••• ••• •••••• ••••••
Prevention of	Invasive breast cancer		••••••••••••	••••••••••••••	•••••••••••••• ••••••••••••
Prevention of	Osteoporosis		••••••••••••	••••••••••••••
Treatment of	Osteoporosis		••••••••••••	••••••••••••••
Treatment of	Osteoporosis caused by corticosteroid		••• •••••

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Pharmacodynamics

Raloxifene belongs to the selective estrogen receptor modulator (SERM) drug class that exhibits estrogenic effects on bone and lipid metabolism while mediating anti-estrogenic effects on uterine endometrium and breast tissues.⁷ On skeletal tissues, raloxifene stimulates bone-depositing osteoblasts and inhibits bone-resorbing osteoclasts¹² to augument bone mineral density.⁷ Raloxifene produces estrogen-like effects on bone, reducing the resorption of bone and increasing bone mineral density in postmenopausal women, thus slowing the rate of bone loss.^Label In three randomized, placebo-controlled trials in Europe, postmenopausal women receiving raloxifene at variable doses of 30 to 150 mg daily demonstrated significant increases in bone mineral density in the lumbar spine, total hip, femoral neck and total body compared to placebo.⁷ In the MORE and RUTH trials, there were fewer incidences of vertebral fractures in postmeopausal women receiving raloxifene compared to placebo.⁶ In a eight-week study evaluating short-term effects of raloxifene in healthy postmenopausal women, there was a decrease in the bone turnover markers, such as serum alkaline phosphatase level, serum osteocalcin level and urinary calcium excretion.⁷

Raloxifene was shown to inhibit estrogen-dependent proliferation of human breast cancer cells in vitro and development of induced mammary tumors in rats in vivo.⁴ In adult female rats, raloxifene produced a greater regression of the mammary gland than tamoxifen.⁴ The MORE trial was a multicenter, randomized, double-blind clinical trial that investigated the long-term effects of the drug therapy in European and American postmenopausal women receiving raloxifene for 40 months.² Additionally, a reduction in the incidence of invasive breast cancer was also demonstrates in the CORE and RUTH trials.⁶ Study findings demonstrated that compared to placebo, the risk of invasive breast cancer was decreased by 76% among postmenopausal women with osteoporosis. There was a decrease in the risk of estrogen receptor-positive breast cancer by 90% but there was no increase in the risk of endometrial cancer. Unlike hormone replacement therapy, raloxifene does not mediate proliferative or stimulatory effects on endometrial tissue. Findings from both animal and human studies demonstrated no significant changes in the histologic appearance of the endometrium.⁷

Raloxifene promotes estrogen-like effects on lipid metabolism. In a European trial that evaluated lipid profiles following raloxifene therapy over the 24-month period, there were significant decreases in the serum concentrations of total and low-density lipoprotein (LDL) cholesterol over a 24-month period of raloxifene therapy.⁷ Raloxifene is not associated with causing alterations in the serum levels of HDL cholesterol or triglycerides.⁷ As the HDL choesterol level is considered a strong inverse predictor of cardiovascular disease in women, the cardioprotective effects of raloxifene were questioned. Due to limited data on the long-term trials, it is not possible to determine whether the small lipid effects produced by raloxifene correlate with a smaller degree of cardioprotective activity compared with hormone replacement therapy.⁷

Mechanism of action

Raloxifene is a selective estrogen receptor modulator that acts as both an estrogen agonist and antagonist via differential effects on the tissue-specific estrogen receptors. Based on the findings of competitive binding assays, raloxifene displays binding affinity that is similar to that of estradiol⁴, the predominant circulating estrogen.⁹ Estrogens play variable roles at different tissues in females, including the bone, breasts, uterus and liver, by binding to the steroid nuclear hormone receptors, Estrogen Receptor alpha (ERα) or Estrogen Receptor beta (ERβ).⁹ These receptors are normally bound to the Heat Shock Protein 90 (Hsp90) when unbound to the ligand. Ligand binding induces a conformational change in the receptor that promotes dissociation of the receptor from Hsp90, dimerization and translocation into the nucleus. This movement into the nucleus allows the receptor to bind to genomic locations based on sequence recognition of the DNA binding domain, also known as the Estrogen Response Elements (EREs).⁹

In bones, endogenous estrogens normally modulate multiple DNA response elements, including the gene-encoding transforming growth factor-β3 (TGF-β3), which is a cytokine embedded in the bone matrix.¹² TGF-β3 plays an important role in bone remodelling⁸ by working with other cytokines to induce production of osteoblasts, such as IL-6³, and attenuate the activity of osetoclasts. Estrogens typically maintain the bone integrity by inhibiting the cytokines that recruit osteoclasts and oppose the bone-resorbing, Ca2+-mobilizing action of parathyroid hormone. In contrast, estrogens promote osteoblast proliferation, augment the production of TGF-β3 and bone morphogenic proteins, and inhibit apoptosis.¹² Mimicking the action of endogenous estrogen in bone tissues, raloxifene binds to the estrogen receptor to influence gene transcription through interactions with the estrogen response element (ERE) and a distinct DNA target, the raloxifene response element (RRE).⁵ It occupies the same ER ligand binding site as estrogen.¹¹ Upon binding, raloxifene induces a conformational change of the receptor, allowing mediation of direct binding to transcriptional elements by accessory proteins. Increased expression of bone matrix proteins, such as alkaline phosphatase, osteonectin, osteocalcin and collagen may be seen.⁵ The agonistic or antagonistic action of raloxifene depends on the extent of recruitment of coactivators and corepressors to estrogen receptor (ER) target gene promotors.^Label In breast tissues, raloxifene acts as an estrogen receptor antagonist to attenuate the estrogen-dependent proliferative effects of epithelial cell expansion. In addition to the antiproliferative effects, raloxifene prevents the production of cytokines and recruitment of macrophages and lymphocytes into tumor mass.¹⁰

Target	Actions	Organism
AEstrogen receptor	agonist	Humans
AEstrogen receptor beta	agonist	Humans
USerpin B9	Not Available	Humans
UTrefoil factor 1	Not Available	Humans

Absorption

Raloxifene is well absorbed from the gastrointestinal tract, with approximately 60% fo the drug being absorbed following oral administration.¹² Due to the extensive first-pass hepatic metabolism that involves glucuronide conjugation, the absolute oral bioavailability of raloxifene is about 2%.¹² Following oral ingestion of a single dose or multiple dose of raloxifen in healthy postmenopausal women, the mean peak plasma concentrations (Cmax) were 0.50 and 1.36 ng/mL, respectively, and the AUC values were 27.2 and 24.2 ngxhr/mL, respectively. The time to reach Cmax following a single or multiple oral doses were 27.7 and 32.5 hours, respectively.^Label Although not clinically significant, oral ingestion of raloxifene with high-fat meals is thought to increase the systemic bioavailability of the drug⁷ by increasnig the peak plasma concentrations (Cmax) and AUC by 28% and 16%, respectively.^Label

Volume of distribution

Following oral administration of single doses randing from 30 to 150 mg in postmenopausal women, the volume of distribution was about 2348 L/kg. Following oral administration of multiple doses, the value increased to 2853 L/kg. Raloxifene is widely distributed in the tissues. It is not known whether raloxifene is excreted in human milk.^Label

Protein binding

About 95% of raloxifene and its glucuronide metabolites are bound to plasma proteins.^Label Although this is a relatively high protein binding profile, in vitro studies suggest that raloxifene and its metabolites do not significantly interact with binding of highly protein-bound drugs.⁷ FDA Label still advises patients to use raloxifene with caution co-administering with other highly protein-bound drugs.^Label

Metabolism

Raloxifene is reported to undergo metabolism in the intestines and liver devoid of cytochrome P450 pathway.⁷ It is extensively metabolized, where less than 1% of the total dose exists as unchanged compound.^Label It mainly undergoes first-pass metabolism to form glucuronide conjugates, raloxifene-4'-glucuronide (raloxifene-4'-β-glucuronide), raloxifene-6-glucuronide (raloxifene-6-β-glucuronide), and raloxifene-6,4'-diglucuronide. No other metabolites have been detected in human plasma. The terminal log-linear portions of the plasma concentration curves for raloxifene and the glucuronides are generally parallel. This is consistent with interconversion of raloxifene and the glucuronide metabolites.^Label

Hover over products below to view reaction partners

• Raloxifene
  • Raloxifene-4′-glucuronide + Raloxifene-6, 4′-diglucuronide + Raloxifene-6-glucuronide

Route of elimination

Raloxifene predominantly undergoes fecal excretion, with less than 0.2% of the dose being excreted in the urine as unchanged form of the compound and less than 6% of the dose being excreted as glucuronide conjugates. Co-administration with cholestyramine, a bile acid sequestrant, was shown to reduce the enterohepatic recycling of raloxifene by 60%.¹²

Half-life

The average plasma elimination half-life of raloxifene ranges from 27 to 32 hours.^7,12 The prolonged half-life has been attributed to the drug's reversible systemic metabolism and significant enterohepatic cycling.⁷

Clearance

Following intravenous administration, raloxifene was shown to be cleared at a rate approximating hepatic blood flow. The apparent oral clearance is reported to be 44.1 L/kgxhr. The clearance can range from 40 to 60L/kgxhr following chronic dosing. In healthy postmenopausal women receiving multiple oral dose, the mean clearance was 47.4 L/kgxhr. Apparent clearance can be reduced by 56% in patients with hepatic impairment.^Label

Adverse Effects

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Toxicity

LD₅₀ and Overdose

The oral LD₅₀ value in rats is > 5000 mg/kg, which is about 810 times the human dose.^MSDS In monkeys, no mortality was seen after a single oral dose of 1000 mg/kg.^Label No cases of raloxifene overdose have been reported during clinical trials. A rare postmarketing report of a non-fatal overdose after oral ingestion of 1.5 g has been reported. Common adverse events of leg cramps, hot flushes, and dizziness have been reported with the use of raloxifene at doses of greater than 180 mg. More serious adverse event of venous thromboembolic events were observed with raloxifene.⁴ Two 18-month-old children accidentally ingested 180 mg of raloxifene and symptoms of ataxia, dizziness, vomiting, rash, diarrhea, tremor, flushing, and elevated alkaline phosphatase levels were reported. There is no known antidote for raloxifene. ^Label

Nonclinical Toxicology

In a two-year mouse carcinogenicity study at raloxifene doses that are higher than the human therapeutic doses, there was an increased incidence of benign and malignant ovarian tumors of granulosa or theca cell origin. Another study showed an increased incidence of testicular interstitial cell tumors, prostatic adenomas, adenocarcinomas, and prostatic leiomyoblastoma in male mice receiving doses higher than human therapeutic doses. There was no evidence of the genotoxic potential of raloxifene in bacterial mutagenicity assays, in vitro rat DNA assays, or other in vitro rodent cell line assays. When assessing effects on the reproductive system of male and female rats, raloxifene caused lack of pregnancy and disruptions in estrous cycles and inhibited ovulation at dose of 0.1 to 10 mg/kg/day. Administration of raloxifene during the preimplantation period at doses greater than 0.1 mg/kg resulted in delayed and disrupted embryo implantation, further leading to prolonged gestation and reduced litter size. There were no effects on sperm production or quality or reproductive performance in male rats. The effects on the fertility by raloxifene were reversible.^Label

Use in special populations

The use of raloxifene in pregnant or nursing women is not advised. Although there are no specific dosing adjustment guidelines, caution should be undertaken when administering raloxifene in geriatric patients or patients with renal or hepatic impairment.^Label

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
Integrate drug-drug interactions in your software
Abemaciclib	The serum concentration of Abemaciclib can be increased when it is combined with Raloxifene.
Acalabrutinib	The serum concentration of Acalabrutinib can be increased when it is combined with Raloxifene.
Acenocoumarol	The serum concentration of Acenocoumarol can be increased when it is combined with Raloxifene.
Acetylcysteine	The excretion of Raloxifene can be decreased when combined with Acetylcysteine.
Adenine	The metabolism of Raloxifene can be decreased when combined with Adenine.

Food Interactions

• Avoid excessive or chronic alcohol consumption. Excessive and chronic alcohol consumption may be associated with vitamin D deficiency.
• Take with or without food. The absorption is unaffected by food.

Products

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Raloxifene Hydrochloride	4F86W47BR6	82640-04-8	BKXVVCILCIUCLG-UHFFFAOYSA-N

Product Images

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International/Other Brands

Keoxifene

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Act Raloxifene	Tablet	60 mg	Oral	Teva Italia S.R.L.	2012-06-19	Not applicable
Evista	Tablet	60 mg/1	Oral	Physicians Total Care, Inc.	2000-05-11	Not applicable
Evista	Tablet	60 mg/1	Oral	PD-Rx Pharmaceuticals, Inc.	1998-01-06	2018-07-17
Evista	Tablet, film coated	60 mg	Oral	Substipharm	2020-12-17	Not applicable
Evista	Tablet	60 mg/1	Oral	Eli Lilly Nederland B.V.	1998-01-06	Not applicable

Generic Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Apo-raloxifene	Tablet	60 mg	Oral	Apotex Corporation	2009-03-31	Not applicable
Jamp Raloxifene	Tablet	60 mg	Oral	Jamp Pharma Corporation	2024-06-28	Not applicable
PMS-raloxifene	Tablet	60 mg	Oral	Pharmascience Inc	2011-09-19	2020-04-22
Raloxifene	Tablet, film coated	60 mg/1	Oral	Avera McKennan Hospital	2016-05-09	2017-05-24
Raloxifene	Tablet, film coated	60 mg/1	Oral	Actavis Pharma Company	2015-06-18	Not applicable

Unapproved/Other Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End	Region	Image
EVISTA 60 MG TABLET, 28 ADET	Raloxifene (60 mg)	Tablet	Oral	DAİİCHİ SANKYO İLAÇ TİC. LTD. ŞTİ.	2013-01-29	2020-12-29

Categories

ATC Codes

G03XC01 — Raloxifene

• G03XC — Selective estrogen receptor modulators
• G03X — OTHER SEX HORMONES AND MODULATORS OF THE GENITAL SYSTEM
• G03 — SEX HORMONES AND MODULATORS OF THE GENITAL SYSTEM
• G — GENITO URINARY SYSTEM AND SEX HORMONES

Drug Categories

• BCRP/ABCG2 Substrates
• Benzene Derivatives
• Benzylidene Compounds
• Bone Density Conservation Agents
• Cytochrome P-450 CYP2B6 Inhibitors
• Cytochrome P-450 CYP2B6 Inhibitors (strong)
• Cytochrome P-450 CYP2C8 Inhibitors
• Cytochrome P-450 CYP2C8 Inhibitors (strength unknown)
• Cytochrome P-450 CYP3A Inhibitors
• Cytochrome P-450 CYP3A4 Inhibitors
• Cytochrome P-450 CYP3A4 Inhibitors (strength unknown)
• Cytochrome P-450 Enzyme Inhibitors
• Estrogen Agonist-antagonists
• Estrogen Agonist/Antagonist
• Estrogen Antagonists
• Estrogen Receptor Modulators
• Genito Urinary System and Sex Hormones
• Hormone Antagonists
• Hormones, Hormone Substitutes, and Hormone Antagonists
• OATP1B1/SLCO1B1 Substrates
• OATP1B3 substrates
• P-glycoprotein substrates
• Selective Estrogen Receptor Modulators
• Sex Hormones and Modulators of the Genital System
• Stilbenes
• UGT1A1 Substrates

Chemical TaxonomyProvided by Classyfire

Description

This compound belongs to the class of organic compounds known as aryl-phenylketones. These are aromatic compounds containing a ketone substituted by one aryl group, and a phenyl group.

Kingdom

Organic compounds

Super Class

Organic oxygen compounds

Class

Organooxygen compounds

Sub Class

Carbonyl compounds

Direct Parent

Aryl-phenylketones

Alternative Parents

3-aroylthiophenes / 1-benzothiophenes / Thiophene carboxylic acids and derivatives / Phenoxy compounds / Phenol ethers / Benzoyl derivatives / Alkyl aryl ethers / 1-hydroxy-2-unsubstituted benzenoids / Piperidines / Heteroaromatic compounds / Trialkylamines / Azacyclic compounds / Organopnictogen compounds / Organic oxides / Hydrocarbon derivatives

show 5 more

Substituents

1-benzothiophene / 1-hydroxy-2-unsubstituted benzenoid / 3-aroylthiophene / Alkyl aryl ether / Amine / Aromatic heteropolycyclic compound / Aryl-phenylketone / Azacycle / Benzenoid / Benzothiophene / Benzoyl / Ether / Heteroaromatic compound / Hydrocarbon derivative / Monocyclic benzene moiety / Organic nitrogen compound / Organic oxide / Organoheterocyclic compound / Organonitrogen compound / Organopnictogen compound / Phenol / Phenol ether / Phenoxy compound / Piperidine / Tertiary aliphatic amine / Tertiary amine / Thiophene / Thiophene carboxylic acid or derivatives

show 18 more

Molecular Framework

Aromatic heteropolycyclic compounds

External Descriptors

1-benzothiophenes, N-oxyethylpiperidine (CHEBI:45355)

Affected organisms

• Humans and other mammals

Chemical Identifiers

UNII

YX9162EO3I

CAS number

84449-90-1

InChI Key

GZUITABIAKMVPG-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]benzoyl}-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

References

Synthesis Reference

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

US20070100147

General References

1. Heringa M: Review on raloxifene: profile of a selective estrogen receptor modulator. Int J Clin Pharmacol Ther. 2003 Aug;41(8):331-45. [Article]
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. [Article]
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. [Article]
4. Balfour JA, Goa KL: Raloxifene. Drugs Aging. 1998 Apr;12(4):335-41; discussion 342. [Article]
5. Clemett D, Spencer CM: Raloxifene: a review of its use in postmenopausal osteoporosis. Drugs. 2000 Aug;60(2):379-411. [Article]
6. Moen MD, Keating GM: Raloxifene: a review of its use in the prevention of invasive breast cancer. Drugs. 2008;68(14):2059-83. [Article]
7. Scott JA, Da Camara CC, Early JE: Raloxifene: a selective estrogen receptor modulator. Am Fam Physician. 1999 Sep 15;60(4):1131-9. [Article]
8. Yang NN, Venugopalan M, Hardikar S, Glasebrook A: Identification of an estrogen response element activated by metabolites of 17beta-estradiol and raloxifene. Science. 1996 Aug 30;273(5279):1222-5. [Article]
9. Palmisano BT, Zhu L, Stafford JM: Role of Estrogens in the Regulation of Liver Lipid Metabolism. Adv Exp Med Biol. 2017;1043:227-256. doi: 10.1007/978-3-319-70178-3_12. [Article]
10. Yaghjyan L, Colditz GA: Estrogens in the breast tissue: a systematic review. Cancer Causes Control. 2011 Apr;22(4):529-40. doi: 10.1007/s10552-011-9729-4. Epub 2011 Feb 1. [Article]
11. Diez-Perez A: Selective estrogen receptor modulators (SERMS). Arq Bras Endocrinol Metabol. 2006 Aug;50(4):720-34. [Article]
12. 35. (2012). In Rang and Dale's Pharmacology (7th ed., pp. 438-439). Edinburgh: Elsevier/Churchill Livingstone. [ISBN:978-0-7020-3471-8]
13. EVISTA (raloxifene hydrochloride) Tablet for Oral Use - FDA Label [Link]

External Links

Human Metabolome Database

HMDB0014624

KEGG Compound

C07228

PubChem Compound

5035

PubChem Substance

46506514

ChemSpider

4859

BindingDB

19441

RxNav

72143

ChEBI

8772

ChEMBL

CHEMBL81

ZINC

ZINC000000538275

Therapeutic Targets Database

DAP000792

PharmGKB

PA451221

Guide to Pharmacology

GtP Drug Page

PDBe Ligand

RAL

RxList

RxList Drug Page

Drugs.com

Drugs.com Drug Page

PDRhealth

PDRhealth Drug Page

Wikipedia

Raloxifene

PDB Entries

1err / 1qkn / 2jfa / 2qxs / 2y05 / 7kbs / 7ndo / 7opn / 7orc / 7ujc

FDA label

Download (286 KB)

MSDS

Download (507 KB)

Clinical Trials

Clinical Trials

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Phase	Status	Purpose	Conditions	Count	Start Date	Why Stopped	100+ additional columns
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Not Available	Completed	Not Available	Adenocarcinomas / Esophageal Cancer / Squamous Cell Carcinoma (SCC)	1	somestatus	stop reason	just information to hide
Not Available	Completed	Not Available	Osteoporosis	3	somestatus	stop reason	just information to hide
Not Available	Completed	Not Available	Postmenopausal Osteoporosis	1	somestatus	stop reason	just information to hide
Not Available	Completed	Prevention	Breast Cancer	2	somestatus	stop reason	just information to hide
Not Available	Completed	Supportive Care	Breast Cancer / Menopausal Symptoms / Osteoporosis	1	somestatus	stop reason	just information to hide

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Pharmacoeconomics

Manufacturers

• Eli lilly and co

Packagers

• AQ Pharmaceuticals Inc.
• A-S Medication Solutions LLC
• Atlantic Biologicals Corporation
• Cardinal Health
• Eli Lilly & Co.
• Kaiser Foundation Hospital
• Lilly Del Caribe Inc.
• Murfreesboro Pharmaceutical Nursing Supply
• PD-Rx Pharmaceuticals Inc.
• Physicians Total Care Inc.
• Prepak Systems Inc.
• Resource Optimization and Innovation LLC

Dosage Forms

Form	Route	Strength
Tablet, coated	Oral	60 mg
Tablet, film coated	Oral
Tablet	Oral	60.000 mg
Tablet	Oral	60 mg
Tablet	Oral	60 mg/1
Tablet, film coated	Oral	60 mg
Tablet, coated	Oral	60 mg/1
Tablet, film coated	Oral	60 mg/1
Tablet, film coated	Oral	60.0 mg

Prices

Unit description	Cost	Unit
Evista 60 mg tablet	4.37USD	tablet

DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US5393763	No	1995-02-28	2012-07-28
CA2158400	No	2006-10-24	2015-09-15
CA2101356	No	1998-11-17	2013-07-27
US6458811	No	2002-10-01	2017-03-10
US6894064	No	2005-05-17	2017-03-10
US6797719	No	2004-09-28	2017-03-10
US8030330	No	2011-10-04	2017-03-10

Properties

State

Solid

Experimental Properties

Property	Value	Source
melting point (°C)	268-272	MSDS
water solubility	Insoluble	MSDS
logP	5.2	Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.000512 mg/mL	ALOGPS
logP	5.45	ALOGPS
logP	5.46	Chemaxon
logS	-6	ALOGPS
pKa (Strongest Acidic)	9	Chemaxon
pKa (Strongest Basic)	8.42	Chemaxon
Physiological Charge	1	Chemaxon
Hydrogen Acceptor Count	5	Chemaxon
Hydrogen Donor Count	2	Chemaxon
Polar Surface Area	70 Å2	Chemaxon
Rotatable Bond Count	7	Chemaxon
Refractivity	135.48 m3·mol-1	Chemaxon
Polarizability	52.55 Å3	Chemaxon
Number of Rings	5	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	No	Chemaxon
Ghose Filter	No	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	Yes	Chemaxon

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 inhibitor	Non-inhibitor	0.9071
CYP450 2D6 inhibitor	Inhibitor	0.8932
CYP450 2C19 inhibitor	Inhibitor	0.8986
CYP450 3A4 inhibitor	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

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted GC-MS Spectrum - GC-MS	Predicted GC-MS	splash10-006t-9112200000-194dfc7c577ba3e76b98
LC-MS/MS Spectrum - LC-ESI-QFT , negative	LC-MS/MS	splash10-0229-0035900000-dcf0b4afb1abd2691c7c
LC-MS/MS Spectrum - LC-ESI-QFT , positive	LC-MS/MS	splash10-0229-6600900000-ea14790ae9aed263379b
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0229-0301900000-70b96a0ec076b464e797
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-00di-0000900000-7ea9552268d1a2db4c2d
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-022i-2416900000-84c9a80a9c13d15a5392
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-03k9-0108900000-72c83bf00049c1b1c454
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0ir1-5900200000-0f28a4039005ae56fb9f
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0006-2059200000-718db7005510569d47bb
Predicted 1H NMR Spectrum	1D NMR	Not Applicable
Predicted 13C NMR Spectrum	1D NMR	Not Applicable

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å2)	Source type	Source
[M-H]-	228.884389	predicted	DarkChem Lite v0.1.0
[M-H]-	210.23293	predicted	DeepCCS 1.0 (2019)
[M+H]+	229.316089	predicted	DarkChem Lite v0.1.0
[M+H]+	212.59091	predicted	DeepCCS 1.0 (2019)
[M+Na]+	228.492889	predicted	DarkChem Lite v0.1.0
[M+Na]+	218.68407	predicted	DeepCCS 1.0 (2019)

Targets

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Binding Properties

×

Property	Measurement	pH	Temperature (°C)	References
EC 50 (nM)	2.4	7.4	22	A28344 / A28352
EC 50 (nM)	4.32	7.5	22	A28357
EC 50 (nM)	22	N/A	N/A	A28361
IC 50 (nM)	4	N/A	N/A	A27495
IC 50 (nM)	22	7.4	22	A27496 / A28344 / A28352
IC 50 (nM)	0.7	N/A	N/A	A28340
IC 50 (nM)	1.8	N/A	N/A	A28341 / A28345 / A28346 / A28347 / A28348 / A28349 / A28350 / A28351 / A28356 / A28359 / A28363
IC 50 (nM)	7	N/A	N/A	A28343
IC 50 (nM)	0.73	N/A	N/A	A28353
IC 50 (nM)	0.89	N/A	N/A	A28354
IC 50 (nM)	0.46	N/A	N/A	A28358
IC 50 (nM)	20.6	7.5	22	A28360
IC 50 (nM)	24	N/A	N/A	A28363
IC 50 (nM)	222	N/A	N/A	A28363
IC 50 (nM)	0.3	N/A	N/A	A28364
Ki (nM)	0.22	N/A	N/A	A28339
Ki (nM)	0.4	N/A	N/A	A28342
Ki (nM)	0.03	N/A	N/A	A28355
Ki (nM)	0.37	7.5	22	A28357
Ki (nM)	2	N/A	N/A	A28362

Details

Binding Properties1. Estrogen receptor

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Agonist

General Function

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. Ligand-dependent nuclear transactivation involves either direct homodimer binding to a palindromic estrogen response element (ERE) sequence or association with other DNA-binding transcription factors, such as AP-1/c-Jun, c-Fos, ATF-2, Sp1 and Sp3, to mediate ERE-independent signaling. Ligand binding induces a conformational change allowing subsequent or combinatorial association with multiprotein coactivator complexes through LXXLL motifs of their respective components. Mutual transrepression occurs between the estrogen receptor (ER) and NF-kappa-B in a cell-type specific manner. Decreases NF-kappa-B DNA-binding activity and inhibits NF-kappa-B-mediated transcription from the IL6 promoter and displace RELA/p65 and associated coregulators from the promoter. Recruited to the NF-kappa-B response element of the CCL2 and IL8 promoters and can displace CREBBP. Present with NF-kappa-B components RELA/p65 and NFKB1/p50 on ERE sequences. Can also act synergistically with NF-kappa-B to activate transcription involving respective recruitment adjacent response elements; the function involves CREBBP. Can activate the transcriptional activity of TFF1. Also mediates membrane-initiated estrogen signaling involving various kinase cascades. Essential for MTA1-mediated transcriptional regulation of BRCA1 and BCAS3 (PubMed:17922032). Maintains neuronal survival in response to ischemic reperfusion injury when in the presence of circulating estradiol (17-beta-estradiol/E2) (By similarity)

Specific Function

14-3-3 protein binding

Gene Name

ESR1

Uniprot ID

P03372

Uniprot Name

Estrogen receptor

Molecular Weight

66215.45 Da

References

1. Khovidhunkit W, Shoback DM: Clinical effects of raloxifene hydrochloride in women. Ann Intern Med. 1999 Mar 2;130(5):431-9. [Article]
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. [Article]
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. [Article]
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. [Article]
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. [Article]
6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
7. Scott JA, Da Camara CC, Early JE: Raloxifene: a selective estrogen receptor modulator. Am Fam Physician. 1999 Sep 15;60(4):1131-9. [Article]
8. Matsumoto T: [Selective estrogen receptor modulators (SERMs)]. Clin Calcium. 2006 Sep;16(9):1520-25. [Article]
9. Moen MD, Keating GM: Raloxifene: a review of its use in the prevention of invasive breast cancer. Drugs. 2008;68(14):2059-83. [Article]

Binding Properties

×

Property	Measurement	pH	Temperature (°C)	References
EC 50 (nM)	341	7.4	22	A28344 / A28352
EC 50 (nM)	4.32	7.5	22	A28357
IC 50 (nM)	43	N/A	N/A	A27495
IC 50 (nM)	260	7.4	22	A27496 / A28344 / A28352
IC 50 (nM)	15	N/A	N/A	A28340
IC 50 (nM)	12	N/A	N/A	A28341 / A28345 / A28346 / A28347 / A28348 / A28349 / A28350 / A28351 / A28356
IC 50 (nM)	470	N/A	N/A	A28343
IC 50 (nM)	18.9	N/A	N/A	A28353
IC 50 (nM)	1.6	N/A	N/A	A28354
IC 50 (nM)	1.9	N/A	N/A	A28365
IC 50 (nM)	8.2	N/A	N/A	A28359 / A28363
IC 50 (nM)	557	7.5	22	A28360
IC 50 (nM)	6.9	N/A	N/A	A28364
Ki (nM)	10	N/A	N/A	A28339
Ki (nM)	4.3	N/A	N/A	A28342
Ki (nM)	4.5	N/A	N/A	A28355
Ki (nM)	2.74	7.5	22	A28357
Ki (nM)	23	N/A	N/A	A28362

Details

Binding Properties2. Estrogen receptor beta

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Agonist

General Function

Nuclear hormone receptor. Binds estrogens with an affinity similar to that of ESR1/ER-alpha, and activates expression of reporter genes containing estrogen response elements (ERE) in an estrogen-dependent manner (PubMed:20074560)

Specific Function

DNA binding

Gene Name

ESR2

Uniprot ID

Q92731

Uniprot Name

Estrogen receptor beta

Molecular Weight

59215.765 Da

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. [Article]
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. [Article]
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. [Article]
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. [Article]
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. [Article]
6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]

Details3. Serpin B9

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

General Function

Granzyme B inhibitor

Specific Function

cysteine-type endopeptidase inhibitor activity involved in apoptotic process

Gene Name

SERPINB9

Uniprot ID

P50453

Uniprot Name

Serpin B9

Molecular Weight

42403.185 Da

References

1. Krieg AJ, Krieg SA, Ahn BS, Shapiro DJ: Interplay between estrogen response element sequence and ligands controls in vivo binding of estrogen receptor to regulated genes. J Biol Chem. 2004 Feb 6;279(6):5025-34. Epub 2003 Nov 14. [Article]

Details4. Trefoil factor 1

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

General Function

Stabilizer of the mucous gel overlying the gastrointestinal mucosa that provides a physical barrier against various noxious agents. May inhibit the growth of calcium oxalate crystals in urine

Specific Function

growth factor activity

Gene Name

TFF1

Uniprot ID

P04155

Uniprot Name

Trefoil factor 1

Molecular Weight

9149.435 Da

References

1. Krieg AJ, Krieg SA, Ahn BS, Shapiro DJ: Interplay between estrogen response element sequence and ligands controls in vivo binding of estrogen receptor to regulated genes. J Biol Chem. 2004 Feb 6;279(6):5025-34. Epub 2003 Nov 14. [Article]

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Drug created at June 13, 2005 13:24 / Updated at October 10, 2024 12:49