Raloxifene

Synonyms :
(2-(4-Hydroxyphenyl)-6-hydroxybenzo(b)thien-3-yl)(4-(2-(1-piperidinyl)ethoxy)phenyl)methanone, Keoxifene, LY 139481, RAL, Raloxifene, Raloxifeno, Raloxifenum

Status : approved

Category

Bone Density Conservation Agents

Therapeutic Classification

OTHER SEX HORMONES AND MODULATORS OF THE GENITAL SYSTEM

GENITO URINARY SYSTEM AND SEX HORMONES
SEX HORMONES AND MODULATORS OF THE GENITAL SYSTEM
OTHER SEX HORMONES AND MODULATORS OF THE GENITAL SYSTEM
Estrogen Antagonists

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]

Used

For 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.

Mechanism Of Action

Raloxifene 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.

Dosage

Form Route Strength
Tablet oral 60 mg
Tablet, film coated oral 60 mg

Pharmacodynamics

Raloxifene, 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.

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

Absorption

Approximately 60% of an oral dose is absorbed, but presystemic glucuronide conjugation is extensive. Absolute bioavailability of raloxifene is 2.0%

Half Life

27.7

Protein Binding

95%

Elimination Route

Raloxifene is primarily excreted in feces, and less than 0.2% is excreted unchanged in urine.

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

Volume of Distribution

* 2348 L/kg [oral administration of single doses ranging from 30 to 150 mg]

Chemical Classification

This compound belongs to the class of organic compounds known as 3-aroylthiophenes. These are thiophenes which are substituted by an aroyl group at the 3-position.

3-aroylthiophenes

Organic compounds

Organoheterocyclic compounds

Thiophenes

3-aroylthiophenes

Salt : Raloxifene Hydrochloride

Chemical Name

(2-(4-Hydroxyphenyl)-6-hydroxybenzo(b)thien-3-yl)(4-(2-(1-piperidinyl)ethoxy)phenyl)methanone

Brands

name Dosage form Country
Act Raloxifene tablet Canada
Apo-raloxifene tablet Canada
Evista tablet US
Evista tablet US
Evista tablet US
Evista tablet US
Evista (60mg) tablet Canada
PMS-raloxifene tablet Canada
Raloxifene tablet, film coated US
Raloxifene tablet Canada
Raloxifene Hydrochloride tablet US
Raloxifene Hydrochloride tablet, film coated US
Raloxifene Hydrochloride tablet, film coated US
Raloxifene Hydrochloride tablet, film coated US
Raloxifene Hydrochloride tablet, film coated US
Raloxifene Hydrochloride tablet US
Raloxifene Hydrochloride tablet US
Raloxifene Hydrochloride tablet US
Raloxifene Hydrochloride tablet, film coated US
Teva-raloxifene tablet Canada

Drug Drug Interactions

  •  Cholestyramine  : Bile Acid Sequestrants may decrease the absorption of Raloxifene.
  •  Colesevelam  : Bile Acid Sequestrants may decrease the absorption of Raloxifene.
  •  Colestipol  : Bile Acid Sequestrants may decrease the absorption of Raloxifene.
  •  Levothyroxine  : Raloxifene may decrease the absorption of Levothyroxine.
  •  Ospemifene  : Selective Estrogen Receptor Modulators may enhance the adverse/toxic effect of Ospemifene. Ospemifene may also enhance adverse/toxic effects of other Selective Estrogen Receptor Modulators. Selective Estrogen Receptor Modulators may diminish the therapeutic effect of Ospemifene. Ospemifene may also diminish the therapeutic effects of other Selective Estrogen Receptor Modulators.

Food Interactions

  • Avoid alcohol., Take without regard to meals.

Calculated Property

kind Value Source
logP 5.45 ALOGPS
logS -6 ALOGPS
Water Solubility 5.12e-04 g/l ALOGPS
logP 5.69 ChemAxon
IUPAC Name 2-(4-hydroxyphenyl)-3-{4-[2-(piperidin-1-yl)ethoxy]benzoyl}-1-benzothiophen-6-ol ChemAxon
Traditional IUPAC Name raloxifene ChemAxon
Molecular Weight 473.583 ChemAxon
Monoisotopic Weight 473.166079047 ChemAxon
SMILES OC1=CC=C(C=C1)C1=C(C(=O)C2=CC=C(OCCN3CCCCC3)C=C2)C2=C(S1)C=C(O)C=C2 ChemAxon
Molecular Formula C28H27NO4S ChemAxon
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 ChemAxon
InChIKey InChIKey=GZUITABIAKMVPG-UHFFFAOYSA-N ChemAxon
Polar Surface Area (PSA) 70 ChemAxon
Refractivity 135.48 ChemAxon
Polarizability 52.55 ChemAxon
Rotatable Bond Count 7 ChemAxon
H Bond Acceptor Count 5 ChemAxon
H Bond Donor Count 2 ChemAxon
pKa (strongest acidic) 8.89 ChemAxon
pKa (strongest basic) 7.95 ChemAxon
Physiological Charge 1 ChemAxon
Number of Rings 5 ChemAxon
Bioavailability 1 ChemAxon
Rule of Five 0 ChemAxon
Ghose Filter 0 ChemAxon
MDDR-Like Rule 1 ChemAxon

Affected organism

Humans and other mammals

Target within organism

  • Estrogen receptor : in Human
  • Estrogen receptor beta : in Human