At nanomolar concentrations, raloxifene fully agonistically activates the TGF beta 3 promoter. In transient transfection studies, raloxifene acts as a pure estrogen antagonist to suppress the expression of the vitellogenin promoter, which contains the estrogen response element[1]. With Ki values ranging from 0.87 to 1.4 nM, raloxifene is a strong uncompetitive inhibitor of the oxidation of phthalazine, vanillin, and nicotine by human liver aldehyde oxidase[2]. Raloxifene has a Ki value of 51 nM and is also a noncompetitive inhibitor of an aldehyde oxidase-catalyzed reduction process of a molecule containing hydroxamic acid[2]. Raloxifene (0-80 μM; 48 hours) dramatically reduced the viability of mouse mmmary carcinoma BJMC3879luc2 cells in a concentration-dependent manner[5].

In ovariectomized (OVX) rats, raloxifene (3 mg/kg; once daily) has a limited effect on uterine wet weight and low estrogenic activity on bone resorption and serum cholesterol[3]. In the proximal tibia and distal femur, raloxifene (oral dosage; 0.1 mg/kg–10 mg/kg; 5 weeks) enhances bone mineral density. In ovariectomized (OVX) rats, it lowers serum cholesteroloral with an ED50 of 0.2 mg/kg[4]. Raloxifene (subcutaneously implanted mini-osmotic pumps; 18 or 27 mg/kg; once daily; 6 weeks) dramatically reduces the number of lymph node metastases in addition to dramatically suppressing tumor sizes in mice[5].

Cell Viability Assay[5]
Cell Types: BJMC3879luc2 cells
Tested Concentrations: 0 μM, 10 μM, 20 μM, 40 μM, 80 μM
Incubation Duration: 48 hrs (hours)
Experimental Results: decreased BJMC3879luc2 cell viability.

Animal/Disease Models: Syngeneic balb/c (Bagg ALBino) mouse with BJMC3879luc2 cells[5]
Doses: 18 or 27 mg/kg
Route of Administration: subcutaneously (sc) implanted mini-osmotic pumps
Experimental Results: Inhibited tumor growth in mice.

Absorption, Distribution and Excretion
Raloxifene is well absorbed from the gastrointestinal tract, with approximately 60% fo the drug being absorbed following oral administration. Due to the extensive first-pass hepatic metabolism that involves glucuronide conjugation, the absolute oral bioavailability of raloxifene is about 2%. 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. Although not clinically significant, oral ingestion of raloxifene with high-fat meals is thought to increase the systemic bioavailability of the drug by increasnig the peak plasma concentrations (Cmax) and AUC by 28% and 16%, respectively.
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%.
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.
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.
It is not known whether raloxifene crosses the human placenta. The molecular weight (about 474 for the free base) and the long elimination half life suggest that the drug will cross to the embryo-fetus. However, the high plasma protein binding might limit the exposure.
Raloxifene undergoes extensive first-pass glucuronidation and enterohepatic circulation, and peak plasma concentrations of the glucuronide conjugates of raloxifene are achieved more rapidly than peak plasma concentrations of the parent drug. Following oral administration of a single 120- or 150-mg dose of raloxifene hydrochloride, peak plasma concentrations of raloxifene and its glucuronide conjugates are achieved at 6 and 1 hour, respectively. Plasma concentrations of raloxifene's glucuronide conjugates exceed those of the parent drug, and the time to achieve maximum concentrations of the drug and glucuronide metabolites depends on the extent and rate of systemic interconversion and enterohepatic circulation. Following oral administration of radiolabeled raloxifene, less than 1% of total circulating radiolabeled material in plasma represented parent drug.
The apparent volume of distribution following oral administration of single doses of raloxifene hydrochloride 30-150 mg is 2348 L/kg, suggesting extensive tissue distribution. The volume of distribution reportedly is not dose dependent over a dosage range of 30-150 mg daily.
Raloxifene is excreted principally in feces as unabsorbed drug and via biliary elimination as glucuronide conjugates, which subsequently are metabolized by bacteria in the GI tract to the parent drug. Following oral administration, less than 6 or 0.2% of a raloxifene dose is excreted as glucuronide conjugates or parent drug, respectively, in urine.
For more Absorption, Distribution and Excretion (Complete) data for Raloxifene (11 total), please visit the HSDB record page.

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Metabolism / Metabolites
Raloxifene is reported to undergo metabolism in the intestines and liver devoid of cytochrome P450 pathway. It is extensively metabolized, where less than 1% of the total dose exists as unchanged compound. 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.
Biotransformation and disposition of raloxifene in humans have been determined following oral administration of (14)C-labeled raloxifene. 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. Unconjugated raloxifene comprises less than 1% of the total radiolabeled material in 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.
Raloxifene undergoes extensive first-pass metabolism to the glucuronide conjugates raloxifene 4'-glucuronide, 6-glucuronide, and 6,4'-diglucuronide. Metabolism of raloxifene does not appear to be mediated by cytochrome P-450 enzymes, since metabolites other than glucuronide conjugates have not been identified.
Raloxifene has known human metabolites that include [6,7-Dihydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-yl][4-(2-piperidinoethoxy)phenyl]methanone, Raloxifene 6-O-glucuronide, and [2-(3,4-dihydroxyphenyl)-6-hydroxy-1-benzothiophen-3-yl]-[4-(2-piperidin-1-ylethoxy)phenyl]methanone.

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Biological Half-Life
The average plasma elimination half-life of raloxifene ranges from 27 to 32 hours. The prolonged half-life has been attributed to the drug's reversible systemic metabolism and significant enterohepatic cycling.
The plasma elimination half-life of raloxifene at steady-state averages 32.5 hours (range: 15.8-86.6 hours).
Raloxifene and its glucuronide conjugates are interconverted by reversible systemic metabolism and enterohepatic cycling, thereby prolonging its plasma elimination half-life to 27.7 hours after oral dosing.

Toxicity Summary
IDENTIFICATION AND USE: Raloxifene is used for the treatment and prevention of osteoporosis in postmenopausal women and for the reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis. HUMAN STUDIES: No fatalities associated with raloxifene overdose have been reported. In postmarketing reports, adverse reactions were reported in approximately half of the adults who took >/= 180 mg raloxifene HCl and included leg cramps and dizziness. Raloxifene therapy is associated with an increased risk of venous thromboembolic events such as deep-vein thrombosis and pulmonary embolism. Increased risk of death due to stroke occurred in a trial in postmenopausal women with documented coronary heart disease or at increased risk for major coronary events. A few cases of jaw bone osteonecrosis have been associated with raloxifene. Two 18-month-old children each ingested raloxifene HCl 180 mg, symptoms reported included ataxia, dizziness, vomiting, rash, diarrhea, tremor, and flushing, as well as elevation in alkaline phosphatase. Raloxifene may cause fetal toxicity when administered to pregnant women. Effects on reproductive function are expected because raloxifene is an estrogen agonist-antagonist. ANIMAL STUDIES: Mortality was not observed in rats or mice following single oral doses of raloxifene hydrochloride 5000 mg/kg, or in monkeys following single oral doses of raloxifene hydrochloride 1000 mg/kg. In a 21-month carcinogenicity study in mice, there was an increased incidence of ovarian tumors in female mice given oral raloxifene hydrochloride 9-242 mg/kg daily and an increased incidence of testicular interstitial cell tumors, prostatic adenomas, and adenocarcinomas in male mice given raloxifene hydrochloride 41 or 210 mg/kg daily. In studies in rats using raloxifene hydrochloride, doses of 0.1-10 mg/kg during gestation and lactation delayed and disrupted parturition, decreased neonatal survival and altered physical development, sex- and age-specific reductions in growth and changes in pituitary hormone content, and decreased lymphoid compartment size in offspring were observed. Disruption of parturition, which resulted in maternal and progeny morbidity and/or death, was observed in rats given raloxifene hydrochloride 10 mg/kg. While ovarian or vaginal pathology was not observed in adult offspring (4 months of age), uterine hypoplasia and reduced fertility were noted. In reproductive studies in rabbits using raloxifene hydrochloride, doses of 0.1 mg/kg or more resulted in abortion and a low rate of fetal heart anomalies (i.e., ventricular septal defects). In rabbits using raloxifene doses of 10 mg/kg or more (at least 4 times the recommended dose in humans on a mg/sq m basis), hydrocephaly was observed in the fetuses. In female rats, at doses of 0.1 to 10 mg/kg/day, raloxifene disrupted estrous cycles and inhibited ovulation. These effects of raloxifene were reversible. When male and female rats were given daily doses >/=5 mg/kg prior to and during mating, no pregnancies occurred. In reproductive studies in rats using raloxifene hydrochloride doses of 1 mg/kg or more, retardation of fetal development and developmental abnormalities (i.e., wavy ribs, kidney cavitation) were observed. Raloxifene was not mutagenic in in vitro or in vivo studies, including the Ames microbial test with and without metabolic activation, the unscheduled DNA synthesis assay in rat hepatocytes, the mouse lymphoma assay for mammalian cell mutation, the chromosomal aberration assay in Chinese hamster ovary cells, the sister chromatid exchange assay in Chinese hamsters, and the micronucleus test in mice.

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Protein Binding
About 95% of raloxifene and its glucuronide metabolites are bound to plasma proteins. 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. FDA Label still advises patients to use raloxifene with caution co-administering with other highly protein-bound drugs.

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Interactions
The manufacturer states that concomitant use of systemic estrogens with raloxifene currently is not recommended because of the lack of experience from prospective clinical trials with such use.
Concomitant administration of raloxifene and ampicillin results in a 28% decrease in peak plasma concentration and a 14% decrease in the extent of absorption of raloxifene. These changes in raloxifene absorption are consistent with decreased enterohepatic cycling associated with a reduction of enteric bacteria. Because systemic exposure and the elimination rate of raloxifene are not affected, raloxifene may be given concomitantly with ampicillin. In raloxifene-treated women with osteoporosis, concomitant administration of amoxicillin did not affect the plasma concentrations of raloxifene. Raloxifene may be given concomitantly with amoxicillin.
While the effect of long-term administration of raloxifene in conjunction with warfarin has not been studied and the drug reportedly does not affect the protein binding of the anticoagulant, concomitant administration of single doses of raloxifene and warfarin has resulted in a 10% decrease in prothrombin time compared with administration of warfarin alone. In raloxifene-treated women with osteoporosis, concomitant administration of warfarin did not affect the plasma concentrations of raloxifene. If the drugs are used concomitantly, the patient and prothrombin time should be monitored closely and the dosage of the anticoagulant adjusted accordingly.
Administration of cholestyramine and raloxifene results in a 60% decrease in the absorption and enterohepatic cycling of raloxifene. The manufacturer states that raloxifene should not be administered with cholestyramine. Although not studied specifically, other anion-exchange resins would also be expected to decrease the absorption and enterohepatic cycling of raloxifene.
Raloxifene is more than 95% bound to plasma proteins. The manufacturer states that concomitant administration of raloxifene with other highly protein-bound drugs is not expected to affect the plasma concentrations of raloxifene. In raloxifene-treated women with osteoporosis, concomitant administration of other highly protein-bound drugs (eg, gemfibrozil) did not affect the plasma concentrations of raloxifene. Raloxifene reportedly does not affect the protein binding of phenytoin, tamoxifen, or warfarin in vitro. The manufacturer states that caution is advised if raloxifene is used concomitantly with other highly protein-bound drugs such as diazepam, diazoxide, or lidocaine.

[1]. Estrogen and raloxifene stimulate transforming growth factor-beta 3 gene expression in rat bone: a potential mechanism for estrogen- or raloxifene-mediated bone maintenance. Endocrinology, 1996. 137(5): p. 2075-84.

[2]. Obach, R.S., Potent inhibition of human liver aldehyde oxidase by raloxifene. Drug Metab Dispos, 2004. 32(1): p. 89-97.

[3]. Sato, M., M.K. Rippy, and H.U. Bryant, Raloxifene, tamoxifen, nafoxidine, or estrogen effects on reproductive and nonreproductive tissues in ovariectomized rats. FASEB J, 1996. 10(8): p. 905-12.

[4]. Raloxifene (LY139481 HCI) prevents bone loss and reduces serum cholesterol without causing uterine hypertrophy in ovariectomized rats. J Clin Invest, 1994. 93(1): p. 63-9.

[5]. Raloxifene inhibits tumor growth and lymph node metastasis in a xenograft model of metastatic mammary cancer.BMC Cancer. 2010 Oct 19;10:566.

Therapeutic Uses
Estrogen Antagonists; Selective Estrogen Receptor Modulators; Bone Density Conservation Agents
/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Raloxifene is included in the database.
Evista is indicated for the treatment and prevention of osteoporosis in postmenopausal women. /Included in US product label/
Evista is indicated for the reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis. /Included in US product label/
For more Therapeutic Uses (Complete) data for Raloxifene (14 total), please visit the HSDB record page.

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Drug Warnings
Use of tamoxifen has been associated with increased rates of cataracts and cataract surgery. In the STAR study, fewer cataracts (RR 0.79; 95% confidence interval: 0.68-0.92) and cataract surgeries (RR 0.82; 95% confidence interval: 0.68-0.99) occurred in those receiving raloxifene than in those receiving tamoxifen.
Use of raloxifene did not affect the risk of coronary events in a study in postmenopausal women with coronary heart disease (CHD) or risk factors for CHD (RUTH study). In the STAR study, the incidence of ischemic heart disease (i.e., myocardial infarction, severe angina, acute ischemic syndrome) in those receiving raloxifene was similar to the incidence in those receiving tamoxifen.
The percentage of sexually active women was lower with raloxifene compared with tamoxifen at nearly every assessment point over the 5-year study duration; among sexually active women, there were increased reports of difficulty with sexual arousal, interest and enjoyment in women receiving raloxifene.
Syncope or development of a varicose vein condition1 has occurred in up to 2.3% of patients receiving raloxifene in clinical studies. In clinical trials, peripheral edema occurred in up to 14.1% of raloxifene-treated women.
For more Drug Warnings (Complete) data for Raloxifene (25 total), please visit the HSDB record page.

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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. On skeletal tissues, raloxifene stimulates bone-depositing osteoblasts and inhibits bone-resorbing osteoclasts to augument bone mineral density. 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. 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. In the MORE and RUTH trials, there were fewer incidences of vertebral fractures in postmeopausal women receiving raloxifene compared to placebo. 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. 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_. In adult female rats, raloxifene produced a greater regression of the mammary gland than [tamoxifen]. 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. Additionally, a reduction in the incidence of invasive breast cancer was also demonstrates in the CORE and RUTH trials. 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. 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. Raloxifene is not associated with causing alterations in the serum levels of HDL cholesterol or triglycerides. 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.

C28H27NO4S.HCL

510.04

509.142

82640-04-8

Raloxifene;84449-90-1

5035

Light yellow to yellow solid powder

1.285g/cm3

728.2ºC at 760 mmHg

143-147ºC

394.2ºC

1.654

6.815

2

6

7

34

655

0

GZUITABIAKMVPG-UHFFFAOYSA-N

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

[6-hydroxy-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl]-[4-(2-piperidin-1-ylethoxy)phenyl]methanone

LY-156758; LY-139481; LY 156758; LY139481; LY156758 (Keoxifene) HCl; LY 139481; trade names: Evista; Keoxifene; RALOX

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.90 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (4.90 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (4.90 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 1% methylcellulose: 30mg/mL

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 (Please use freshly prepared in vivo formulations for optimal results.)