Molecule

Drug Groups

approved; investigational

Description

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

Indication

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.

Pharmacology

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.

Affected Organisms

Biotransformation

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

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

Distribution

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

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

References

External Links