| 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. |
| 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. |
| 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. |
| Absorption |
Approximately 60% of an oral dose is absorbed, but presystemic
glucuronide conjugation is extensive. Absolute bioavailability of
raloxifene is 2.0% |
| Volume of distribution |
- 2348 L/kg [oral administration of single doses ranging from 30 to 150 mg]
|
| Protein binding |
95% |
| 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 |
| Route of elimination |
Raloxifene is primarily excreted in feces, and less than 0.2% is excreted unchanged in urine. |
| Half life |
27.7 |
| 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
|
| Toxicity |
Not Available |
