タモキシフェン 化學(xué)特性,用途語,生産方法
用途
男性または女性ホルモン製剤そのままでは男性化ないし女性化の副作用が現(xiàn)れることが多いため，それらの副作用の少ない薬剤として乳癌治療にタモキシフェン(ノルバデックス)やメピチオスタン(チオデロン)が最近開発され，用いられている。
効能
抗悪性腫瘍薬, エストロゲン受容體調(diào)節(jié)薬
説明
In 1966, ICI Pharmaceuticals (now AstraZeneca) first synthesized
tamoxifen in the hope of developing a morning-after
contraceptive pill. The UK patent for this compound was in
place in 1962, whereas the US patent was repeatedly denied
until the 1980s. Tamoxifen was approved for a fertility treatment
but it was not proven as useful in regulating human
contraception. Even though there was a link between estrogen
and breast cancer, developing a cancer treatment was not
a priority at the time. In 1971, the first clinical study showed
a convincing effect of tamoxifen in treating advanced breast
cancer. From 1971 to 1977, this drug was neither clinically nor
financially remarkable. In 1980s, however, publications first
showed that tamoxifen, in addition to chemotherapy,
improved survival for patients with early stage breast cancer. In
1998, the meta-analysis by the Oxford-based Early Breast
Cancer Trialists’ Collaborative Group showed that tamoxifen
did indeed save lives in early breast cancer. In 2001, tamoxifen
sales were over $1.024 billion. Since the expiration of the
patent in 2002, it is now widely available as a generic drug. By
2004, tamoxifen was the best selling hormonal drug for the
treatment of breast cancer.
化學(xué)的特性
White Crystalline Solid
使用
A nonsteroidal estrogen antagonist of interest in the treatment of some forms of breast cancer. Tamoxifen is a Protein Kinase C inhibitor, and induces apoptosis in human malignant glioma cell lines
適応癥
Tamoxifen (Nolvadex) is a synthetic antiestrogen used in the treatment of breast cancer.
Normally, estrogens act by binding to a cytoplasmic protein
receptor, and the resulting hormone–receptor complex
is then translocated into the nucleus, where it induces
the synthesis of ribosomal RNA (rRNA) and messenger
RNA (mRNA) at specific sites on the DNA of the target
cell. Tamoxifen also avidly binds to estrogen receptors and
competes with endogenous estrogens for these critical sites.
The drug–receptor complex has little or no estrogen agonist
activity.Tamoxifen directly inhibits growth of human
breast cancer cells that contain estrogen receptors but has
little effect on cells without such receptors.
世界保健機(jī)関（WHO）
Tamoxifen is an anti-estrogen agent used mainly to treat breast
cancer. Tamoxifen is listed in the WHO Model List of Essential Drugs.
一般的な説明
Tamoxifen is a selective estrogen response modifier (SERM), protein kinase C inhibitor and anti-angiogenetic factor. Tamoxifen is a prodrug that is metabolized to active metabolites 4-hydroxytamoxifen (4-OHT) and endoxifen by cytochrome P450 isoforms CYP2D6 and CYP3A4. In breast cancer, the gene repressor activity of tamoxifen against ERBB2 is dependent upon PAX2. Blocks estradiol-stimulated VEGF production in breast tumor cells.
作用機(jī)序
Tamoxifen is slowly absorbed, and maximum serum
levels are achieved 4 to 7 hours after oral administration.
The drug is concentrated in estrogen target tissues, such
as the ovaries, uterus, vaginal epithelium, and breasts.
Hydroxylation and glucuronidation of the aromatic
rings are the major pathways of metabolism; excretion
occurs primarily in the feces.
薬物動態(tài)學(xué)
Circulating levels of the demethylated metabolite at steady state are up to twice the level of the parent drug, because the elimination half-life of N-demethyl tamoxifen is 14 days, compared with 7 days for tamoxifen. Tamoxifen demonstrates only weak estrogenic effects at several sites, including the endometrium and bone, and on the lipid profile. Tamoxifen undergoes rapid N-dem ethylation to its major metabolite, N-dem ethyltamoxifen, by CYP3A4 and via CYP2D6 to its minor metabolite, 4-hydroxytam oxifen. Evidence suggests that 4-hydroxytamoxifen is the active metabolite of tamoxifen, with a higher binding affinity than the parent drug for the ER
臨床応用
Tamoxifen is a SERM that is used as an antiestrogen in the treatment of estrogen-dependent breas Tcancer following prim ary treatment (c hemotherapy and/or surgery).
副作用
Tamoxifen administration is associated with few
toxic side effects, most frequently hot flashes (in
10–20% of patients) and occasionally vaginal dryness or
discharge. Mild nausea, exacerbation of bone pain, and
hypercalcemia may occur.
安全性プロファイル
Confirmed human
carcinogen. Moderately toxic by ingestion
and intraperitoneal routes. Human systemic
effects by an unspecified route: nausea or
vomiting, leukopenia, thrombocytopenia,
and skin changes. An experimental
teratogen. Other experimental reproductive
effects. Human mutation data reported.
When heated to decomposition it emits
toxic fumes of NOx.
発がん性
Tamoxifen is known to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in humans.
タモキシフェン 上流と下流の製品情報(bào)
原材料
準(zhǔn)備製品