|Company Name:||Tocopharm Co., Ltd. Gold|
|Product Categories:||Pharmaceutical material and intermeidates;Taxotere;Active Pharmaceutical Ingredients;Antineoplastics;Antineoplastic;Plant extracts;Herb extract;API;chemical reagent;pharmaceutical intermediate;phytochemical;reference standards from Chinese medicinal herbs (TCM).;standardized herbal extract;inhibitor;Anti-cancer&immunity;Inhibitors|
|Docetaxel Chemical Properties|
|Docetaxel Usage And Synthesis|
|Pharmacology and toxicology||Docetaxel belongs to taxanes-class drugs. It can boost the assembly of tubulin dimer into microtubules while stabilizing the microtubules by preventing the process of de-polymerization. Owing to the above two effects, it block the cells in the G2 and M phase, and thereby inhibiting cancer cell mitosis and proliferation. The pharmacological effect of docetaxel is higher than paclitaxel with former one having an intracellular concentration 3-fold of the later one. It also has a long retention time inside the cell and has a microtubule affinity twice of that of paclitaxel. As a microtubule-stabilizing agents and assembly accelerator, it has a 2 times larger activity than paclitaxel. As a microtubule depolymerization inhibitor, its activity is also 2 times larger than that of paclitaxel. In the in vitro tests of anti-tumor activity, it has been confirmed that the anti-tumor activity docetaxel is 1.3 to 12 times as high as paclitaxel. Clinical studies show that docetaxel has a much better efficacy than paclitaxel in treating the anthracycline-resistant breast cancer. |
Docetaxel is by far the most effective drug in the second-line treatment of anthracycline resistant breast cancer; in the mono-therapy of non-small cell lung cancer and combination chemotherapy, docetaxel is also one of the most effective drugs. Genetic Toxicity: In the chromosome aberration test of CHO-K1 cells and the micronucleus test of mouse bone marrow, docetaxel induced faulting. But no mutagenic effects were observed in the Ames test and the CHO / HGPRT gene mutation assay. Reproductive toxicity: intravenous injection of 0.3 mg/kg docetaxel into rats (body surface area conversion, approximately 1/50 of the recommended clinical dose) causes no damage effects on, but can cause a decreased testicular weight. The results has a good correlation with results of the repeated administration test of 10 cycles (administered once every 21 days, 6 months); when the intravenous administrated dose of rats and dogs were 5mg / kg and 0.375mg/kg(according to body surface area conversion, approximately equivalent to the recommended clinical dose of 1/3 and 1/15, respectively), respectively, testicular atrophy and degeneration were observed. Increasing the administration number of rats at low doses treatment causes similar effects. Taking docetaxel during the pregnancy can cause fetal damage. When rats and rabbits during organogenesis were administrated with docetaxel ≥0.3mg/kg/day and 0.03mg/kg/day (according to body surface area conversion, equivalent to the recommended daily clinical dose of 1/50 and 1/300, respectively), embryo toxicity and fetal toxicity (exhibited as intrauterine death, increased fetal absorption, increased fetal weight loss and delayed ossification) were observed. Above doses can also cause maternal toxicity. There are no enough and strictly controlled clinical studies in pregnant women. If the patient applied this drug during pregnancy or get pregnant during the application of this product, they should be told about its potential danger to fetus and the potential risk of abortion. Women of childbearing potential in using this treatment should be avoided getting pregnant. It is still unclear whether docetaxel is excreted from human milk. Given that many drugs can be excreted in human milk, and docetaxel may cause serious adverse reactions on nursing infants, mothers should stop breast-feeding before using this product.
|Pharmacokinetics||It is reported in the literature about the pharmacokinetic study on cancer patients in dose of 20-115mg/m2. When the dose is at 75-115mg/m2, during the 1-2 hours of intravenous infusion, the AUC is dose-related. Pharmacokinetic characteristics of the product is in line with a three-compartment pharmacokinetic model with α, β, γ half-life being 4 minutes, 36 minutes and 11.1 hours, respectively. The rapid decrease of drug concentration during the initial phase shows that the drugs are being distributed surrounding chamber; the later phase is partly due to the slowly elimination of drug from the peripheral compartment. Intravenous infusion of 100 mg/m2 docetaxel within 1 hour results in the mean peak concentration being 3.7 μg/mL and AUC being 4.6 μg/mL?h; the total body clearance and steady-state distribution is 21 L/h/m2 and 113L, respectively. Docetaxel and its metabolites are mainly excreted in feces. The amount of faeces and urine, respectively, accounted for about 75% and 6% of the given dose; only a small portion excreted in its prototype. In vitro studies have shown that docetaxel plasma protein binding rate is higher than about 94-97%; dexamethasone did not affect the binding of docetaxel and protein. In vitro studies have also shown that docetaxel is metabolized by CYP3A4 isoenzyme, which can be inhibited by CYP3A4 metabolic inhibitor.
|Indications||It is used for treating locally advanced or metastatic breast cancer. 2. It is suitable for the treatment of locally advanced or metastatic non-small cell lung cancer, even after the failure of cisplatin-based chemotherapy.
|Dosage and Administration||Docetaxel can only applied through intravenous infusion. All patients should orally take glucocorticoids such as dexamethasone before receiving the treatment of docetaxel. Take it one day before the docetaxel infusion, take a daily dose of 16mg and continue for at least 3 days in order to prevent allergic reactions and fluid retention. The recommended dose of docetaxel is 70-75mg/m2 with intravenous infusion for one hour and be taken once every three weeks. According to the calculated dosage for the patient, apply the required dose by syringe; dilute it to 5% dextrose injection or 0.9% sodium chloride injection; gently shake, mix uniformly with the final concentration of no more than 0.74mg/ml.
|Side effects and adverse reactions||1. Bone marrow suppression: neutropenia is the most common adverse reactions, and often more severe adverse reactions (less than 500/mm3). This process is reversible and does not accumulate. According to the report of literature, there is and neutropenia-related fever and infection. Anemia is seen in the majority of cases, and severe thrombocytopenia occurred in few cases. 2. Allergies: severe allergic reaction may occur in some cases characterized by hypotension and bronchospasm, which requires interruption of treatment. Stopping infusion and seeking for treatment immediately can restore the patients. There may also be some mild allergic reactions in some light symptoms such as blush, erythema accompanied with or without erythema with itching, chest tightness, back pain, dyspnea, and drug-induced fever or chills. 3. Skin reactions usually include erythema which is mainly seen in the hands, feet and skin rash which may occur in the local arm, face and chest, sometimes accompanied by itching. The rash usually may occur after a week of docetaxel infusion, but can be recovered before the next infusion. Severe symptoms such as rash, peeling appear rarely. There may be also the occurrence of (toe) fingernail lesion behaved with lighten pigmentation, and sometimes pain and fall-off of nails also occur. 4. Body fluid retention includes edema and very few reported cases of pleural effusion, ascites, pericardial effusion, increased capillary permeability, and increased weight. After 4 cycles of treatment or a cumulative doses of 400mg/m2, fluid retention occurs in lower limb, and might develop to whole-body edema together with a over 3 kg increase in weight. After stopping docetaxel therapy, fluid retention gradually disappears. In order to reduce fluid retention, patients should be given prophylactic use of corticosteroids. 5. You may get gastrointestinal reactions like nausea, vomiting or diarrhea. 6. Few cases of neurotoxicity have been reported in clinical trials. 7. Cardiovascular adverse reactions include hypotension, sinus tachycardia, palpitations, pulmonary edema, and hypertension. 8. Other adverse reactions include: alopecia, asthenia, mucositis, joint pain and muscle pain, hypotension, and injection site reactions. 9. Patents of normal liver function during treatment can also suffer elevated transaminases and bilirubin whose relationship with docetaxel is unclear.
|Precautions||[Contraindications] (1) Patients who has a severe allergic history to docetaxel or Tween-80; (2) Patients who have leukocyte counts less than 1500/mm3;(3) Patients who suffers severe liver function impairment. |
[Pregnant women and lactating women drug] there are currently no adequate and strictly controlled clinical studies in pregnant women. If the patient applied this drug during pregnancy or get pregnant during the application of this product, they should be told about its potential danger to fetus and the potential risk of abortion. Women of childbearing potential in using this treatment should be avoided getting pregnant. It is still unclear whether docetaxel is excreted from human milk. Given that many drugs can be excreted in human milk, and docetaxel may cause serious adverse reactions on nursing infants, mothers should stop breast-feeding before using this product.
[Medication of children] The efficacy and safety of docetaxel used in children is not clear.
[Drug interactions] In vitro studies showed that CYP3A4 inhibitors may interfere with the metabolism of the product, so patients should be cautious when taking together with these drugs (such as ketoconazole, erythromycin, cyclosporine, etc.).
[Overdose] once overdose, the patient should be transferred into a special care unit for close monitoring of vital organ function. When docetaxel overdose occurs, there is no antidote available. Any expected excess of major complications include neutropenia, skin reactions and paresthesias.
The above information is edited by the Chemicalbook of Dai Xiongfeng.
|Chemical Properties||Melting point 232 °C (methanol). [A] D-36° (C = 0.74, ethanol). Maximal UV absorption: 230,275,283nm (ε 14800, 1730, 1670).
|Application||1. It can be used as anticancer drugs for treating uterine cancer. |
2. Antitumor herbal, for the treatment of metastatic breast cancer and non-small cell lung cancer.
3. Docetaxel can be used for studying antibiotics, cell biology, cell signaling, neuroscience, apoptosis and cell cycle. Docetaxel is also used for study hair loss caused by paclitaxel chemotherapy, and for prevention and treatment the non-small cell lung cancer for patients who are forbidden to use standard chemotherapy. Docetaxel has also been widely used to study the effects of hypoxia inducible factor 2α in -1α on androgen-insensitive prostate cancer cells.
|Production methods||Semi-synthesis of it uses the 10-deacetylbaccatin III as raw materials extracted from the needle-like leaves of the European yew Taxus baccata L. 10-deacetylbaccatin III can be converted to the compound product (I) after acylation. |
Cinnamic acid (330mg, 2.24mmo1), dicyclohexyl carbodiimide (DCC, 460mg, 2.24mmo1), the compound (I) (500mg, 0.56mmo1) and 4-dimethylaminopyridine (68mg, 0.56mmo1) are stirred under argon at 70 °C for 15h. Cooled, filtered, and the filter pellet should be further washed with toluene. Combine the filtrate and washings and concentrate under reduced pressure. Add methylene chloride to the residue; wash with 2% aqueous hydrochloric acid; dry it using anhydrous magnesium sulfate. The solvent is further evaporated under reduced pressure, and the remaining 1g residue is purified by column chromatography with the elution of hexane - ethyl acetate (7: 3) to obtain 540mg compound (II), yield 94%.
N-chloro-N-sodium carbamate (47mg, 0.27mmo1) and silver nitrate (91.4mg, 0.54mmo1) or other metal salts are stirred in 2mL acetonitrile, toluene or pyridine, stirred for 10 mins. Compound (II) (50mg, 0.049mmo1) and 0.537ml of osmium tetroxide in t-butanol and (0.1mmol/ 1 ML) are further added and stirred at room temperature or at 4 °C (darkness) for 24h. Filter, add 0.22 mmol sodium bisulfite (2.5% aqueous solution) and stir for 3h. The reaction solution is further extracted with dichloromethane and the extract is dried and concentrated. Use thin layer chromatography to separate and elute it with 7: 3 ether - hexane to give the compound (III) and its isomer. Chemical compound (III) can have a yield of up to 25%. Using mercury nitrate instead of silver nitrate can further increase the yield.
Compound (III) (0.13mmo1) and 150mg of zinc powder is reacted at 60°C for 2 h in 5 mL methanol-acetic acid (1: 1). Filter, concentrate, extracted with ethyl acetate. Purify it by chromatography with the elution of 7: 3 dichloromethane - methanol to obtain the product in 90% yield.
|Chemical Properties||Off-white Cryst|
|Usage||antineoplastic;binds to microtubules|
|Docetaxel Preparation Products And Raw materials|