Estrogen Receptor/ER

Fulvestrant（Faslodex®）由6-脱氢诺龙乙酸酯分四步合成（总收率35%）。在关键的C-C键形成步骤[1]中，使用了由市售9-溴壬-1-烯衍生的二茂锆的催化剂控制、室温、非对映选择性1,6-加成反应。

在大鼠和猪尾猴中，单次注射ICI 182780油悬浮液后，持续的抗雌激素作用都很明显。在体内，ICI 182780在裸鼠体内用MCF-7和Br10人乳腺癌异种移植物证明了其抗肿瘤活性。单次注射ICI 182780提供的抗肿瘤疗效相当于至少4周的每日他莫昔芬治疗。ICI 182780的特性将这种纯抗雌激素确定为主要候选药物，用于评估完全停止雌激素对内分泌反应性人类乳腺癌症的潜在治疗益处[2]。

Absorption, Distribution and Excretion
Fulvestrant was rapidly cleared by the hepatobiliary route with excretion primarily via the feces (approximately 90%). Renal elimination was negligible (less than 1%).
3 to 5 L/kg
Peak plasma concentrations of fulvestrant are attained approximately 7 days after IM administration and persist for at least 1 month. Steady-state plasma fulvestrant concentrations usually are achieved within 3-6 months when the drug is administered once-monthly by IM injection.
Fulvestrant appears to be rapidly and extensively distributed, principally into the extravascular space
99% (mainly VLDL, LDL, and HDL lipoprotein fractions).
Has been shown to cross the placenta and distribute into milk in rats.
For more Absorption, Distribution and Excretion (Complete) data for FULVESTRANT (8 total), please visit the HSDB record page.

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Metabolism / Metabolites
Metabolism of fulvestrant appears to involve combinations of a number of possible biotransformation pathways analogous to those of endogenous steroids, including oxidation, aromatic hydroxylation, conjugation with glucuronic acid and/or sulphate at the 2, 3 and 17 positions of the steroid nucleus, and oxidation of the side chain sulphoxide. Identified metabolites are either less active or exhibit similar activity to fulvestrant in antiestrogen models. Studies using human liver preparations and recombinant human enzymes indicate that cytochrome P-450 3A4 (CYP 3A4) is the only P-450 isoenzyme involved in the oxidation of fulvestrant; however, the relative contribution of P-450 and non-P-450 routes in vivo is unknown.
Biotransformation and disposition of fulvestrant in humans have been determined following intramuscular and intravenous administration of 14C-labeled fulvestrant. Metabolism of fulvestrant appears to involve combinations of a number of possible biotransformation pathways analogous to those of endogenous steroids, including oxidation, aromatic hydroxylation, conjugation with glucuronic acid and/or sulphate at the 2, 3 and 17 positions of the steroid nucleus, and oxidation of the side chain sulphoxide.
Metabolites of fulvestrant exhibit pharmacologic activity that is similar to or less than that of the parent compound.
In vitro studies indicate that CYP3A4 is the only enzyme involved in fulvestrant oxidation; however, the relative contribution of CYP and non-CYP routes in vivo currently is not known.

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Biological Half-Life
40 days
The elimination half-life of fulvestrant is about 40 days.

Hepatotoxicity
Fulvestrant therapy is said to be associated with serum enzyme elevations in up to 15% of patients, but the elevations are generally asymptomatic, transient and mild, rarely requiring dose adjustment or discontinuation. ALT elevations above 5 times the upper limit of normal occurred in only 1% to 2% of patients. However, specifics on the timing and course of serum enzyme elevations during fulvestrant therapy have not been described. In addition, no cases of clinically apparent liver injury with jaundice were reported in the prelicensure controlled trials of fulvestrant and none have been published since its approval in the United States and more wide-scale use. Nevertheless, the product label for fulvestrant mentions that "hepatitis and liver failure have been reported infrequently (
Likelihood score: E* (unproven but suspected cause of clinically apprent liver injury).

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Protein Binding
99% (mainly VLDL, LDL, and HDL)

[1]. An alternative synthesis of the breast cancer drug fulvestrant (Faslodex®): catalyst control over C-C bond formation. Chem Commun (Camb). 2015;51(80):14866-14868.

[2]. A potent specific pure antiestrogen with clinical potential. Cancer Res. 1991;51(15):3867-3873.

Therapeutic Uses
Antineoplastic Agents; Hormonal Estrogen Antagonists
Fulvestrant is indicated for the treatment of hormone receptor positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy. /Included in US product label/

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Drug Warnings
/Fulvestrant is contraindicated in/ pregnancy, known hypersensitivity to fulvestrant, benzyl alcohol, or any ingredient in the formulation.
Because fulvestrant is administered by IM injection, the drug should not be used in patients with bleeding diatheses or thrombocytopenia or in those receiving anticoagulant therapy.
The most common adverse effects of fulvestrant are adverse GI effects (e.g., nausea, vomiting, constipation, diarrhea, abdominal pain), headache, back pain, vasodilation (hot flushes), and pharyngitis, which occurred in approximately 52, 15, 14, 18, and 16% of patients, respectively, who received the drug in clinical studies.
Other adverse effects occurring in 5-23% of patients receiving fulvestrant (in order of descending frequency) include asthenia, pain, nutritional disorders, bone pain, dyspnea, injection site pain, increased cough, pelvic pain, anorexia, peripheral edema, rash, chest pain, flu syndrome, dizziness, insomnia, fever, paresthesia, urinary tract infection, depression, anxiety, and sweating. Injection site reactions with mild transient pain and inflammation were reported in 7% of patients receiving a single 5-mL injection of fulvestrant in one study and in 27% of those who received two 2.5-mL injections of the drug in another study.
For more Drug Warnings (Complete) data for FULVESTRANT (7 total), please visit the HSDB record page.

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Pharmacodynamics
Fulvestrant for intramuscular administration is an estrogen receptor antagonist without known agonist effects.

C32H47F5O3S

606.77080655098

606.316

C, 63.34; H, 7.81; F, 15.66; O, 7.91; S, 5.28

1316849-17-8

Fulvestrant;129453-61-8;Fulvestrant (R enantiomer);1807900-80-6

104741

White powder ... the solution for injection is a clear, colorless to yellow, viscous liquid

9.2

76.7

2

9

14

41

854

6

C[C@]12CC[C@H]3[C@H]([C@@H]1CC[C@@H]2O)[C@@H](CC4=C3C=CC(=C4)O)CCCCCCCCCS(=O)CCCC(C(F)(F)F)(F)F

VWUXBMIQPBEWFH-WCCTWKNTSA-N

InChI=1S/C32H47F5O3S/c1-30-17-15-26-25-12-11-24(38)21-23(25)20-22(29(26)27(30)13-14-28(30)39)10-7-5-3-2-4-6-8-18-41(40)19-9-16-31(33,34)32(35,36)37/h11-12,21-22,26-29,38-39H,2-10,13-20H2,1H3/t22-,26-,27+,28+,29-,30+,41?/m1/s1

(7R,8R,9S,13S,14S,17S)-13-methyl-7-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,17-diol

1316849-17-8; (7R,8S,9S,13R,14S)-13-methyl-7-[9-[(S)-4,4,5,5,5-pentafluoropentylsulfinyl]nonyl]-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,17-diol;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。