Estrogen Receptor/ER

Fulvestrant (Faslodex®) was synthesized in four steps (35% overall yield) from 6-dehydronandrolone acetate. Catalyst controlled, room temperature, diastereoselective 1,6-addition of the zirconocene derived from commercially available 9-bromonon-1-ene was used in the key C-C bond forming step [1].

Sustained antiestrogenic effects, following a single parenteral dose of ICI 182,780 in oil suspension, were apparent in both rats and pigtail monkeys. In vivo, antitumor activity of ICI 182,780 was demonstrated with xenografts of MCF-7 and Br10 human breast cancers in nude mice. A single injection of ICI 182,780 provided antitumor efficacy equivalent to that of daily tamoxifen treatment for at least 4 weeks. The properties of ICI 182,780 identify this pure antiestrogen as a prime candidate with which to evaluate the potential therapeutic benefits of complete estrogen withdrawal in endocrine-responsive human breast cancer [2].

Absorption, Distribution and Excretion
Fulvestrant is rapidly cleared via the hepatobiliary route, primarily excreted in feces (approximately 90%). Renal clearance is negligible (less than 1%). Peak plasma concentrations are reached approximately 7 days after intramuscular injection of fulvestrant and remain elevated for at least 1 month. Steady-state plasma fulvestrant concentrations are typically reached within 3-6 months after monthly intramuscular injections. Fulvestrant is rapidly and widely distributed, primarily in the extravascular space (99% of which are VLDL, LDL, and HDL lipoprotein components). Fulvestrant has been shown to cross the placenta and distribute in rat milk. For more complete data on the absorption, distribution, and excretion of fulvestrant (8 parameters), please visit the HSDB records page. Metabolism/Metabolites Fulvestrant metabolism appears to involve a combination of multiple possible biotransformation pathways, similar to the metabolic pathways of endogenous steroids, including oxidation, aromatic hydroxylation, binding to glucuronic acid and/or sulfate at positions 2, 3, and 17 of the steroid, and oxidation of the nucleus and side-chain sulfoxides. Identified metabolites exhibit lower activity or similar activity to fulvestrant in anti-estrogenic models. Studies using human liver preparations and recombinant human enzymes have shown that cytochrome P-450 3A4 (CYP 3A4) is the only P-450 isoenzyme involved in fulvestrant oxidation; however, the relative contributions of the P-450 and non-P-450 pathways in vivo remain unclear. Biotransformation and distribution of fulvestrant in humans have been determined following intramuscular and intravenous injection of 14C-labeled fulvestrant. The metabolism of fulvestrant appears to involve a combination of multiple possible biotransformation pathways, similar to those of endogenous steroids, including oxidation, aromatic hydroxylation, binding to glucuronic acid and/or sulfate at positions 2, 3, and 17 of the steroid nucleus, and oxidation of the side-chain sulfoxide. The metabolites of fulvestrant exhibit pharmacological activity similar to or lower than that of the parent compound. In vitro studies have shown that CYP3A4 is the only enzyme involved in the oxidation of fulvestrant; however, the relative contributions of CYP and non-CYP pathways in vivo are currently unclear. The elimination half-life of fulvestrant is approximately 40 days.

Hepatotoxicity
It has been reported that fulvestrant treatment can cause elevated serum enzymes in up to 15% of patients, but these elevations are usually asymptomatic, transient, and mild, rarely requiring dose adjustment or discontinuation. Only 1% to 2% of patients experience ALT elevations exceeding 5 times the upper limit of normal. However, the specific timing and process of serum enzyme elevations during fulvestrant treatment are not detailed. Furthermore, no cases of clinically significant liver injury with jaundice were reported in pre-marketing controlled trials of fulvestrant, and no such cases have been reported since its approval and widespread use in the United States. However, the fulvestrant product label states that "reports of hepatitis and liver failure are uncommon (Probability score: E (unproven but suspected cause of clinically significant liver injury)). Protein binding 99% (primarily bound to 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 drug; Hormone estrogen antagonist. Fulvestrant is indicated for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women whose breast cancer has progressed after anti-estrogen therapy. /US product label contains/

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Drug Warnings /Flvestrant is contraindicated in/pregnancy, and in patients with known hypersensitivity to fulvestrant, benzyl alcohol, or any component of the formulation.
Because fulvestrant is administered intramuscularly, it is contraindicated in patients with bleeding disorders, thrombocytopenia, or those receiving anticoagulation therapy.
The most common adverse reactions to fulvestrant are gastrointestinal adverse reactions (e.g., nausea, vomiting, constipation, diarrhea, abdominal pain), headache, back pain, vasodilation (hot flashes), and pharyngitis. In clinical studies, the incidence of these adverse reactions in patients receiving this drug was approximately 52%, 15%, 14%, 18%, and 16%, respectively.
The incidence of other adverse reactions ranges from 5% to 23% (listed in descending order of frequency). Adverse reactions include fatigue, pain, nutritional disorders, bone pain, dyspnea, injection site pain, worsening cough, pelvic pain, anorexia, peripheral edema, rash, chest pain, flu-like symptoms, dizziness, insomnia, fever, paresthesia, urinary tract infection, depression, anxiety, and sweating. One study showed that 7% of patients receiving a single 5 mL fulvestrant injection reported an injection site reaction, manifesting as mild, transient pain and inflammation; another study showed that 27% of patients receiving two 2.5 mL fulvestrant injections reported an injection site reaction. For more complete data on fulvestrant (7 of 7), please visit the HSDB record page. Pharmacodynamics: Fulvestrant for intramuscular injection is an estrogen receptor antagonist and does not have known agonist activity.

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

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

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)