Human Liver Aldehyde Oxidase (AO): Raloxifene HCl inhibits human liver AO activity with a Ki value of 1.2 μM, showing competitive inhibition against AO substrate phthalazine [2]
- Estrogen Receptor α/β (ERα/β): Raloxifene HCl binds to ERα and ERβ as a selective modulator,It exhibits agonist activity in bone tissue and antagonist activity in mammary/uterine tissue [1][3][4]

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].

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1. Inhibition of Human Liver Aldehyde Oxidase ([2]):
- Incubation of human liver cytosolic AO (0.5 mg/mL) with Raloxifene HCl (0.1–10 μM) and AO substrate phthalazine (100 μM) for 60 minutes at 37°C inhibited AO-mediated phthalazine oxidation in a concentration-dependent manner. At 1 μM, inhibition rate was 45%; at 10 μM, inhibition rate reached 90% (measured via HPLC detection of phthalazine metabolite) [2]
2. Antiproliferative Activity in Metastatic Breast Cancer Cells ([5]):
- Treatment of MDA-MB-231 (ER-negative, metastatic breast cancer) cells with Raloxifene HCl (1–50 μM) for 72 hours inhibited cell proliferation with an IC50 of 8 μM (MTT assay). At 20 μM, it induced apoptosis by 35% (Annexin V/PI flow cytometry) and reduced migration capacity by 40% (transwell migration assay) [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].

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1. Stimulation of TGF-β3 Expression in Rat Bone ([1]):
- Ovariectomized (OVX) female Sprague-Dawley rats (250–300 g) were orally administered Raloxifene HCl (1 mg/kg/day) for 14 days. Femoral bone tissue analysis showed that Raloxifene HCl increased TGF-β3 mRNA expression by 60% (real-time PCR) and TGF-β3 protein levels by 55% (Western blot) compared to OVX control. It also increased trabecular bone density by 30% (micro-CT) [1]
2. Effects on Reproductive/Nonreproductive Tissues in OVX Rats ([3]):
- OVX rats were orally treated with Raloxifene HCl (0.1, 1, 10 mg/kg/day) for 21 days. Unlike estrogen (1 μg/kg/day) or tamoxifen (1 mg/kg/day), Raloxifene HCl did not increase uterine wet weight (uterine weight/body weight ratio unchanged vs. OVX control). At 10 mg/kg, it increased tibial bone mineral density (BMD) by 25% and reduced serum LDL cholesterol by 20% [3]
3. Prevention of Bone Loss and Cholesterol Reduction ([4]):
- OVX rats were orally given Raloxifene HCl (1, 5, 10 mg/kg/day) for 8 weeks. The 10 mg/kg dose inhibited femoral bone loss by 40% (BMD measurement) and reduced serum total cholesterol by 25% and triglycerides by 15% (enzymatic assay). No uterine hypertrophy was observed (uterine weight similar to OVX control) [4]
4. Inhibition of Tumor Growth and Metastasis ([5]):
- Female nude mice (6–8 weeks old) were subcutaneously inoculated with 2×10⁶ MDA-MB-231 cells. When tumors reached 100 mm³, Raloxifene HCl was orally administered at 5, 10, 20 mg/kg/day for 28 days. The 20 mg/kg dose reduced tumor volume by 50% and tumor weight by 45% (measured twice weekly). It also decreased axillary lymph node metastasis rate from 80% (control) to 30% (histological examination) [5]

Human Liver Aldehyde Oxidase (AO) Inhibition Assay ([2]):
The assay was conducted in a 200 μL reaction system containing 50 mM potassium phosphate buffer (pH 7.4), 0.5 mg/mL human liver cytosol (source of AO), 100 μM phthalazine (AO substrate), and Raloxifene HCl (0.1–10 μM). The mixture was incubated at 37°C for 60 minutes, and the reaction was stopped by adding 50 μL of 10% trichloroacetic acid. After centrifugation (10,000×g, 10 minutes), the supernatant was analyzed via HPLC (C18 column) to quantify unmetabolized phthalazine. The Ki value was calculated via Lineweaver-Burk plot analysis of competitive inhibition [2]

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.

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MDA-MB-231 Cell Proliferation, Apoptosis, and Migration Assay ([5]):
1. Proliferation Assay: 96-well plates were seeded with 5×10³ MDA-MB-231 cells/well in RPMI 1640 (10% FBS). After 24 hours, Raloxifene HCl (1–50 μM) was added, and cells were incubated for 72 hours. MTT reagent was added, and absorbance was measured at 570 nm to calculate IC50.
2. Apoptosis Assay: 6-well plates were seeded with 2×10⁵ cells/well, treated with 20 μM Raloxifene HCl for 48 hours. Cells were stained with Annexin V-FITC/PI and analyzed via flow cytometry to count apoptotic cells.
3. Migration Assay: Transwell inserts (8 μm pore) were coated with collagen. 1×10⁴ cells/well (serum-free medium + 20 μM Raloxifene HCl) were added to the upper chamber; medium with 10% FBS was added to the lower chamber. After 24 hours, migrated cells on the lower membrane were stained with crystal violet and counted [5]

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.

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1. OVX Rat Bone TGF-β3 Expression Protocol ([1]):
- Ovariectomy: Female Sprague-Dawley rats (250–300 g) were anesthetized and subjected to bilateral ovariectomy; sham-operated rats served as control.
- Drug Preparation: Raloxifene HCl was dissolved in 0.5% methylcellulose + 0.1% Tween 80.
- Administration: OVX rats were orally gavaged with 1 mg/kg/day Raloxifene HCl or vehicle for 14 days; sham rats received vehicle.
- Sample Collection: Rats were euthanized, femurs were collected for micro-CT (BMD measurement) and RNA/protein extraction (TGF-β3 detection) [1]
2. OVX Rat Tissue Effect Protocol ([3]):
- Ovariectomy: As described in [1]; OVX rats were randomized into 4 groups (n=6/group).
- Administration: Rats were orally gavaged with Raloxifene HCl (0.1, 1, 10 mg/kg/day), estrogen (1 μg/kg/day), or vehicle for 21 days.
- Tissue Analysis: Uterine wet weight was measured; tibial BMD was detected via dual-energy X-ray absorptiometry (DXA); serum LDL cholesterol was quantified via enzymatic assay [3]
3. OVX Rat Bone Loss/Cholesterol Protocol ([4]):
- Ovariectomy: As described in [1]; OVX rats were randomized into 4 groups (n=8/group).
- Administration: Rats were orally gavaged with Raloxifene HCl (1, 5, 10 mg/kg/day) or vehicle for 8 weeks.
- Detection: Femoral BMD was measured via DXA; serum total cholesterol and triglycerides were analyzed via commercial kits [4]
4. MDA-MB-231 Xenograft Protocol ([5]):
- Cell Inoculation: 2×10⁶ MDA-MB-231 cells (suspended in 0.2 mL PBS + 50% Matrigel) were subcutaneously injected into the right flank of female nude mice (6–8 weeks old).
- Administration: When tumors reached 100 mm³, mice were orally gavaged with Raloxifene HCl (5, 10, 20 mg/kg/day) or vehicle for 28 days.
- Tumor/Metastasis Detection: Tumor volume was calculated as (length × width²)/2 twice weekly. After euthanasia, tumors were weighed; axillary lymph nodes were sectioned and stained with H&E to assess metastasis [5]

Absorption, Distribution and Excretion
Raloxifene is well absorbed from the gastrointestinal tract, with approximately 60% of the drug absorbed after oral administration. Due to its extensive first-pass hepatic metabolism (involving glucuronide conjugation), the absolute oral bioavailability of raloxifene is approximately 2%. In healthy postmenopausal women, the mean peak plasma concentration (Cmax) after a single or multiple oral dose of raloxifene was 0.50 and 1.36 ng/mL, respectively, with AUC values of 27.2 and 24.2 ng·hr/mL, respectively. The time to reach Cmax after a single or multiple oral dose was 27.7 hours and 32.5 hours, respectively. Although clinically insignificant, oral administration of raloxifene with a high-fat meal is believed to improve systemic bioavailability, increasing peak plasma concentration (Cmax) and AUC by 28% and 16%, respectively. Raloxifene is primarily excreted in the feces, with less than 0.2% of the dose excreted unchanged in the urine and less than 6% excreted as glucuronide conjugates. Concomitant use with the bile acid sequestrant cholestyramine reduces the enterohepatic circulation of raloxifene by 60%. In postmenopausal women, the volume of distribution after a single oral dose of 30 to 150 mg raloxifene is approximately 2348 L/kg. After multiple oral doses, its clearance increases to 2853 L/kg. Raloxifene is widely distributed in tissues. It is unknown whether raloxifene is excreted into human milk. After intravenous administration, the clearance rate of raloxifene is similar to that of hepatic blood flow. The apparent oral clearance has been reported to be 44.1 L/kg·hr. With prolonged administration, clearance can decrease to 40 to 60 L/kg·hr. In healthy postmenopausal women, the mean clearance after multiple oral doses is 47.4 L/kg·hr. Apparent clearance can be reduced by 56% in patients with hepatic impairment. It is unknown whether raloxifene can cross the human placenta. Its molecular weight (free base approximately 474) and long elimination half-life suggest that the drug may cross the placenta and enter the embryo. However, high plasma protein binding may limit drug exposure. Raloxifene undergoes extensive first-pass glucuronidation and enterohepatic circulation, with peak plasma concentrations of its glucuronide conjugates reached faster than the parent drug. Following a single oral dose of 120 or 150 mg raloxifene hydrochloride, peak plasma concentrations of raloxifene and its glucuronide conjugates were reached at 6 hours and 1 hour, respectively. The plasma concentrations of raloxifene glucuronide conjugates were higher than those of the parent drug, and the time to reach maximum concentrations of the drug and its glucuronide metabolites depended on the extent and rate of systemic interconversion and enterohepatic circulation. After oral administration of radiolabeled raloxifene, the proportion of the parent drug in the total circulating radiolabeled material in plasma was less than 1%. Following a single oral dose of 30–150 mg raloxifene hydrochloride, the apparent volume of distribution was 2348 L/kg, indicating extensive tissue distribution. According to reports, within the daily dose range of 30-150 mg, the volume of distribution is dose-independent. Raloxifene is primarily excreted in feces as unabsorbed drug and also in bile as a glucuronide conjugate, which is subsequently metabolized to the parent drug by bacteria in the gastrointestinal tract. After oral administration, less than 6% and 0.2% of the raloxifene dose are excreted in urine as glucuronide conjugates or unchanged drug, respectively. For more complete data on absorption, distribution, and excretion of raloxifene (11 items in total), please visit the HSDB records page. Metabolism/Metabolites Raloxifene is reportedly metabolized in the intestine and liver, but its metabolic pathway does not involve cytochrome P450. It is extensively metabolized, with less than 1% of the total dose remaining in its original form. Raloxifene is primarily metabolized via first-pass metabolism to glucuronide conjugates, including raloxifene-4'-glucuronide (raloxifene-4'-β-glucuronide), raloxifene-6-glucuronide (raloxifene-6-β-glucuronide), and raloxifene-6,4'-disglucuronide. No other metabolites have been detected in human plasma. The log-linear portions of the plasma concentration curves for raloxifene and its glucuronides are generally parallel. This is consistent with the interconversions between raloxifene and its glucuronide metabolites. Following oral administration of 14C-labeled raloxifene, the biotransformation and distribution of raloxifene in humans have been determined. Raloxifene undergoes extensive first-pass metabolism to glucuronide conjugates: raloxifene-4'-glucuronide, raloxifene-6-glucuronide, and raloxifene-6,4'-disglucuronide. No other metabolites were detected, strongly suggesting that raloxifene is not metabolized via the cytochrome P450 pathway. Free raloxifene in plasma accounts for less than 1% of the total radiolabeled content. The logarithmic linear portions at the ends of the plasma concentration curves for raloxifene and its glucuronide are generally parallel. This is consistent with the interconversion between raloxifene and its glucuronide metabolites. The metabolism of raloxifene does not appear to be mediated by cytochrome P-450 enzymes, as no other metabolites have been found besides the glucuronide conjugate. Known metabolites of raloxifene include [6,7-dihydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl][4-(2-piperidinylethoxy)phenyl] methyl ketone, raloxifene 6-O-glucuronide, and [2-(3,4-dihydroxyphenyl)-6-hydroxy-1-benzothiophen-3-yl]-[4-(2-piperidin-1-ylethoxy)phenyl] methyl ketone.

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Biobiological Half-Life
The mean plasma elimination half-life of raloxifene is 27 to 32 hours. The prolonged half-life of raloxifene is attributed to its reversible systemic metabolism and significant enterohepatic circulation.
The mean steady-state plasma elimination half-life of raloxifene is 32.5 hours (range: 15.8–86.6 hours).
Raloxifene and its glucuronide conjugates can be interconverted through reversible systemic metabolism and enterohepatic circulation, thus prolonging the plasma elimination half-life after oral administration to 27.7 hours.

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Oral Absorption: Due to extensive first-pass metabolism (glucuronidation) in the liver and intestine, the oral bioavailability of raloxifene hydrochloride in humans is approximately 2% [4].
-Plasma Half-Life: In ovariectomized (OVX) rats, the plasma half-life of oral administration of 10 mg/kg raloxifene hydrochloride was 6 hours, with peak plasma concentration at 6 hours. The peak plasma concentration (Cmax) was 80 ng/mL 2 hours after gavage [4]
- Metabolism: Raloxifene hydrochloride is mainly metabolized in the liver by UDP-glucuronyl transferase (UGT) to inactive glucuronide conjugates. Cytochrome P450 enzymes have little effect on its metabolism [2]

Toxicity Summary
Identification and Uses: Raloxifene is used to treat and prevent osteoporosis in postmenopausal women and to reduce the risk of invasive breast cancer in postmenopausal women with osteoporosis. Human Studies: No deaths due to raloxifene overdose have been reported. Post-marketing reports indicate that approximately half of adults taking ≥180 mg of raloxifene hydrochloride reported adverse reactions, including leg cramps and dizziness. Raloxifene treatment is associated with an increased risk of venous thromboembolic events, such as deep vein thrombosis and pulmonary embolism. An increased risk of stroke death was found in a trial in postmenopausal women with a history of coronary artery disease or an increased risk of major coronary events. A small number of cases of osteonecrosis of the jaw have been associated with raloxifene. Two 18-month-old children who ingested 180 mg of raloxifene hydrochloride reported symptoms including ataxia, dizziness, vomiting, rash, diarrhea, tremor, and flushing, as well as elevated alkaline phosphatase. Raloxifene is fetal toxic to pregnant women. As raloxifene is an estrogen agonist-antagonist, it is expected to affect reproductive function. Animal studies: No deaths were observed in rats and mice after a single oral dose of 5000 mg/kg raloxifene hydrochloride, and no deaths were observed in monkeys after a single oral dose of 1000 mg/kg raloxifene hydrochloride. In a 21-month mouse carcinogenicity study, female mice showed an increased incidence of ovarian tumors after daily oral administration of 9–242 mg/kg raloxifene hydrochloride, while male mice showed an increased incidence of testicular interstitial cell tumors, prostate adenomas, and adenocarcinomas after daily oral administration of 41 or 210 mg/kg raloxifene hydrochloride. In rat studies, administration of raloxifene hydrochloride at doses of 0.1–10 mg/kg during pregnancy and lactation delayed and disrupted parturition, reduced neonatal survival, altered pupal physical development, leading to sex- and age-specific slowed growth and development, changes in pituitary hormone levels, and reduced lymphoid tissue volume. Rats administered 10 mg/kg raloxifene hydrochloride experienced birth disturbances, leading to morbidity and/or death in both mothers and pups. While no ovarian or vaginal lesions were observed in adult offspring (4 months of age), uterine hypoplasia and decreased fertility were noted. In rabbit reproductive studies with raloxifene hydrochloride, doses of 0.1 mg/kg or higher resulted in abortion with a low incidence of fetal cardiac malformations such as ventricular septal defects. Fetal hydrocephalus was observed in rabbits treated with raloxifene at doses of 10 mg/kg or higher (at least four times the recommended human dose per mg/m²). In female rats, raloxifene at doses ranging from 0.1 to 10 mg/kg/day disrupted the estrous cycle and inhibited ovulation. These effects of raloxifene were reversible. No pregnancy occurred in male or female rats when administered ≥5 mg/kg raloxifene daily before and during mating. In reproductive studies in rats, fetal growth retardation and developmental abnormalities (e.g., wavy ribs, cavitary kidneys) were observed with doses of raloxifene hydrochloride at 1 mg/kg or higher. Raloxifene has not shown mutagenicity in in vitro and in vivo studies, including the Ames microbial assay with/without metabolic activation, the rat hepatocyte unplanned DNA synthesis assay, the mammalian cell mutation mouse lymphoma assay, the Chinese hamster ovary cell chromosomal aberration assay, the Chinese hamster sister chromatid exchange assay, and the mouse micronucleus assay. Protein Binding: Approximately 95% of raloxifene and its glucuronide metabolites are bound to plasma proteins. Despite the relatively high protein binding rate of raloxifene, in vitro studies have shown no significant interaction between raloxifene and its metabolites and highly protein-bound drugs. The FDA drug label still recommends caution when using raloxifene in combination with other highly protein-bound drugs. Drug Interactions: The manufacturer notes that due to a lack of experience from prospective clinical trials, concomitant use of systemic estrogens with raloxifene is currently not recommended.
Concomitant use of raloxifene and ampicillin results in a 28% decrease in peak plasma concentration of raloxifene and a 14% decrease in absorption. These changes in raloxifene absorption are consistent with reduced enterohepatic circulation due to decreased gut bacteria. Since systemic exposure and elimination of raloxifene are unaffected, raloxifene can be used concurrently with ampicillin. In female patients with osteoporosis receiving raloxifene treatment, concomitant use of amoxicillin does not affect raloxifene plasma concentrations. Raloxifene can be taken concurrently with amoxicillin.
Although the long-term effects of raloxifene and warfarin have not been studied, and the drug has been reported not to affect the protein binding rate of anticoagulants, a single dose of raloxifene and warfarin concurrently can shorten prothrombin time by 10% compared to warfarin alone. In female patients with osteoporosis receiving raloxifene treatment, concomitant use of warfarin does not affect raloxifene plasma concentrations. If these medications are used concurrently, patients and prothrombin time should be closely monitored, and the anticoagulant dosage adjusted accordingly.
Concomitant use of cholestyramine and raloxifene can reduce raloxifene absorption and enterohepatic circulation by 60%. The manufacturer states that raloxifene should not be used concurrently with cholestyramine. Although no specific studies have been conducted, other anion exchange resins are expected to also reduce raloxifene absorption and enterohepatic circulation.
Raloxifene binds to plasma proteins at a rate exceeding 95%. The manufacturer states that concomitant use of raloxifene with other drugs with high protein binding rates is not expected to affect raloxifene plasma concentrations. In female patients with osteoporosis receiving raloxifene treatment, concomitant use of other drugs with high protein binding rates (such as gemfibrozil) does not affect raloxifene plasma concentrations. Raloxifene has been reported not to affect the protein binding of phenytoin, tamoxifen, or warfarin in vitro. The manufacturer notes that caution should be exercised when raloxifene is used concurrently with other drugs with high protein binding rates, such as diazepam, diazoxide, or lidocaine.

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1. In vitro cytotoxicity:
- Raloxifene hydrochloride (1–50 μM) was not cytotoxic to normal human osteoblasts (cell viability >90% vs. control group, MTT assay)[5]
- At concentrations >100 μM, it induced nonspecific cell death in MDA-MB-231 cells (viability <60% vs. control group)[5]
2. In vivo toxicity:
- Ovarian-removed (OVX) rats treated with raloxifene hydrochloride (0.1–10 mg/kg/day) for 8 weeks showed no significant changes in liver function (ALT, AST) or kidney function (BUN, creatinine) compared to the control group[3][4]
- No uterine hypertrophy (a common side effect of estrogen/tamoxifen) was observed in ovariectomized (OVX) rats treated with raloxifene hydrochloride [3][4] - No weight loss or hematological abnormalities (normal white blood cell and platelet counts) were observed in nude mice treated with raloxifene hydrochloride (20 mg/kg/day) for 28 days [5] 3. Plasma protein binding rate: Raloxifene hydrochloride has a high plasma protein binding rate (>98%) in human and rat plasma (as determined by ultrafiltration) [4]

[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 mineral density protectants. ClinicalTrials.gov is a registry and results database that indexes human clinical studies funded by public and private institutions worldwide. The website is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each record on ClinicalTrials.gov includes a summary of the study protocol, including: the disease or condition; the intervention (e.g., the medical product, behavior, or procedure under investigation); the title, description, and design of the study; participation requirements (eligibility criteria); the location of the study; contact information for the study location; and links to relevant information from other health websites, such as the NLM's MedlinePlus (for patient health information) and PubMed (for citations and abstracts of academic articles in the medical field). Raloxifene is indexed in the database. Evista is indicated for the treatment and prevention of osteoporosis in postmenopausal women. /Included in the US product label/
Evista is indicated for reducing the risk of invasive breast cancer in postmenopausal women with osteoporosis. /Included in the US product label/
For more complete therapeutic use data for raloxifene (one of 14), please visit the HSDB record page.

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Drug Warning
Tamoxifen use is associated with an increased incidence of cataracts and cataract surgery.In the STAR study, the incidence of cataracts (RR 0.79; 95% confidence interval: 0.68–0.92) and the rate of cataract surgery (RR 0.82; 95% confidence interval: 0.68–0.99) were both lower in patients treated with raloxifene than in patients treated with tamoxifen.
In a study of postmenopausal women with coronary artery disease (CHD) or risk factors for CHD (the RUTH study), raloxifene use did not affect the risk of coronary events. In the STAR study, the incidence of ischemic heart disease (i.e., myocardial infarction, severe angina, acute ischemic syndrome) was similar in patients treated with raloxifene to that in patients treated with tamoxifen. During the 5-year study period, at almost every assessment, the proportion of sexually active women treated with raloxifene was lower than that of women treated with tamoxifen. Among sexually active women, those taking raloxifene reported difficulties with sexual arousal, sexual interest, and sexual pleasure. In clinical studies, up to 2.3% of patients treated with raloxifene experienced syncope or varicose veins. In clinical trials, up to 14.1% of women treated with raloxifene experienced peripheral edema. For more complete data on drug warnings for raloxifene (25 total), please visit the HSDB records page.

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Pharmacodynamics
Raloxifene belongs to the class of selective estrogen receptor modulators (SERMs). It has estrogen-like effects on bone and lipid metabolism, while also having anti-estrogenic effects on the endometrium and breast tissue. In bone tissue, raloxifene stimulates osteoblasts to deposit bone tissue and inhibits osteoclasts to resorb bone tissue, thereby increasing bone mineral density. Raloxifene has estrogen-like effects on bone, reducing bone resorption and increasing bone mineral density in postmenopausal women, thus slowing bone loss. In three randomized, placebo-controlled trials conducted in Europe, postmenopausal women taking different doses of raloxifene daily (30 to 150 mg) had significantly higher bone mineral density in the lumbar spine, hip, femoral neck, and throughout the body than the placebo group. In the MORE and RUTH trials, the incidence of vertebral fractures in postmenopausal women taking raloxifene was lower than in the placebo group. An eight-week study evaluated the short-term efficacy of raloxifene in healthy postmenopausal women, showing a decrease in bone turnover markers, such as serum alkaline phosphatase levels, serum osteocalcin levels, and urinary calcium excretion. In vitro experiments showed that raloxifene inhibited estrogen-dependent proliferation of human breast cancer cells; in vivo experiments showed that raloxifene inhibited the development of induced mammary tumors in rats. In adult female rats, raloxifene induced greater mammary atrophy than tamoxifen. The MORE trial was a multicenter, randomized, double-blind clinical trial designed to investigate the long-term efficacy of raloxifene treatment in postmenopausal women in Europe and the United States after 40 months. Furthermore, the CORE and RUTH trials also confirmed that raloxifene reduces the incidence of invasive breast cancer. Results showed that, compared to placebo, raloxifene reduced the risk of invasive breast cancer by 76% in postmenopausal women with osteoporosis. The risk of estrogen receptor-positive breast cancer was reduced by 90%, but the risk of endometrial cancer was not increased. Unlike hormone replacement therapy, raloxifene does not have a proliferative or stimulatory effect on endometrial tissue. Both animal and human studies have shown no significant changes in the histological morphology of the endometrium. Raloxifene has estrogen-like effects on lipid metabolism. A European trial evaluating lipid profiles after 24 months of raloxifene treatment showed significant reductions in serum total cholesterol and low-density lipoprotein cholesterol (LDL-C) concentrations during the 24-month treatment period. Raloxifene does not cause changes in serum high-density lipoprotein cholesterol (HDL-C) or triglyceride levels. Because HDL-C levels are considered a strong negative predictor of cardiovascular disease in women, the cardioprotective effect of raloxifene has been questioned. Due to limited long-term trial data, it is not yet possible to determine whether the mild lipid effects of raloxifene are associated with its lower cardioprotective activity compared to hormone replacement therapy.

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1. Drug Classification and Mechanism ([1][3][4]):
- Raloxifene hydrochloride is a selective estrogen receptor modulator (SERM) that acts as an estrogen receptor (ER) agonist in bone (stimulating TGF-β3 expression and maintaining bone density), as an ER agonist in lipid metabolism (lowering LDL cholesterol), and as an ER antagonist in breast/uterine tissue (inhibiting cell proliferation) [1][3][4]
2. Indications ([4][5]):
- It has been approved for the prevention and treatment of postmenopausal osteoporosis (through its anti-bone loss effect). It also showed potential to inhibit metastatic breast cancer (reducing tumor growth and lymph node metastasis) [4][5]
3. Advantages compared to other selective estrogen receptor modulators (SERMs) ([3][4]):
- Unlike tamoxifen or estrogen, raloxifene hydrochloride does not cause uterine hypertrophy, thus reducing the risk of endometrial cancer associated with long-term estrogen/tamoxifen use [3][4]
4. Role of TGF-β3 in bone maintenance ([1]):
- The bone protection mediated by raloxifene hydrochloride is partly achieved by upregulating TGF-β3, which promotes osteoblast differentiation and inhibits osteoclast activity, thereby increasing trabecular bone density [1]

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

C1CCN(CC1)CCOC2=CC=C(C=C2)C(=O)C3=C(SC4=C3C=CC(=C4)O)C5=CC=C(C=C5)O

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.)