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Docetaxel Trihydrate (formerly RP-56976; NSC-628503; trade name Taxotere), the trihydrated form of docetaxel which is a paclitaxel analog, is a tubulin/mitotic inhibitor with a broad spectrum of antineoplastic activities. It has been approved for use in the treatment of many types of cancers.
Physicochemical Properties
| Molecular Formula | C43H53NO14.3H2O |
| Molecular Weight | 861.93 |
| Exact Mass | 861.378 |
| Elemental Analysis | C, 59.92; H, 6.90; N, 1.63; O, 31.55 |
| CAS # | 148408-66-6 |
| Related CAS # | Docetaxel;114977-28-5;Docetaxel-d5 trihydrate |
| PubChem CID | 148123 |
| Appearance | White to off-white solid powder |
| Density | 1.37 g/cm3 |
| Boiling Point | 1016.9ºC at 760 mmHg |
| Melting Point | 186-192ºC |
| Flash Point | 568.8ºC |
| Vapour Pressure | 0mmHg at 25°C |
| LogP | 3.457 |
| Hydrogen Bond Donor Count | 8 |
| Hydrogen Bond Acceptor Count | 17 |
| Rotatable Bond Count | 13 |
| Heavy Atom Count | 61 |
| Complexity | 1660 |
| Defined Atom Stereocenter Count | 11 |
| SMILES | CC1=C2[C@H](C(=O)[C@@]3([C@H](C[C@@H]4[C@]([C@H]3[C@@H]([C@@](C2(C)C)(C[C@@H]1OC(=O)[C@@H]([C@H](C5=CC=CC=C5)NC(=O)OC(C)(C)C)O)O)OC(=O)C6=CC=CC=C6)(CO4)OC(=O)C)O)C)O.O.O.O |
| InChi Key | XCDIRYDKECHIPE-QHEQPUDQSA-N |
| InChi Code | InChI=1S/C43H53NO14.3H2O/c1-22-26(55-37(51)32(48)30(24-15-11-9-12-16-24)44-38(52)58-39(3,4)5)20-43(53)35(56-36(50)25-17-13-10-14-18-25)33-41(8,34(49)31(47)29(22)40(43,6)7)27(46)19-28-42(33,21-54-28)57-23(2)45;;;/h9-18,26-28,30-33,35,46-48,53H,19-21H2,1-8H3,(H,44,52);3*1H2/t26-,27-,28+,30-,31+,32+,33-,35-,41+,42-,43+;;;/m0.../s1 |
| Chemical Name | [(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-acetyloxy-1,9,12-trihydroxy-15-[(2R,3S)-2-hydroxy-3-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoyl]oxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.03,10.04,7]heptadec-13-en-2-yl] benzoate;trihydrate |
| Synonyms | RP56976 (NSC 628503) Trihydrate; RP56976; NSC 628503; RP-56976; NSC628503; RP 56976; Docetaxel hydrate; XRP6976; Docetaxel (Trihydrate); Docetaxel (as trihydrate); RP 56976; CHEBI:59809; NSC-628503; Docetaxel trihydrate, Trade name: Taxotere. |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | Tubulin; microtubule; microtubule depolymerization | ||
| ln Vitro | Cell viability was impacted in a dose-dependent manner by both single and combined treatments with docetaxel trihydrate (RP-56976 trihydrate) and glufosfamide (GLU). In PC-3 and LNCaP cells, the IC50 of GLU is 70±4 μM and 86.8±8 μM, respectively. Conversely, the IC50 of docetaxel alone was 1.46±0.2 nM and 3.08±0.4 nM in PC-3 and LNCaP cells, respectively. When GLU and Docetaxel were co-treated, the IC50 values in PC-3 and LNCaP cells were lowered to 2.7±0.1 nM and 0.75±0.3 nM, respectively [1]. NCI-H460's half-life against cetaxel was 30 nM after 72 hours and 116 nM at 24 hours. On NCI-60 cell plates, the typical IC50 for docetaxel is 14–34 nM, according to data from the DTP data search [2]. | ||
| ln Vivo | The intestinal cell apoptosis induced by Docetaxel Trihydrate (RP-56976 Trihydrate) in female mice was considerably higher in the 14-hour light exposure (HALO) group compared to the 2-HALO group. After receiving docetaxel, the 2-HALO group's Bax expression increased dramatically, but not in the 14-HALO group. Conversely, docetaxel markedly elevated the expression of cleaved Caspase-3 in the 14-HALO group, but not in the 2-HALO group. Furthermore, docetaxel dramatically decreased the expression of survivin protein in the 14-HALO group but not in the 2-HALO group. When compared to the 2-HALO group treated with the same medication, the survivin expression level in the 14-HALO group treated with docetaxel was considerably lower [3]. Whereas docetaxel (DOX) was given intravenously at a dose of 7 mg/kg, piperine (PIP) was given as an intravenous bolus at 3.5 mg/kg, as well as 35 mg/kg and 3.5 mg/kg orally. Rat Sprague-Daley type. Sprague-Dawley rats were coadministered PIP at 35 mg/kg orally and docetaxel at 7 mg/kg by intravenous bolus. Their in vivo exposure is synergistically increased when PIP and docetaxel are used together [4]. | ||
| Enzyme Assay | In Vitro Tubulin Polymerization Assay. [5] Tubulin was prepared as described before. The pig brain microtubule protein was isolated through three cycles of temperature-dependent assembly/disassembly in PEM buffer (pH 6.5, 100 mM PIPES, 2 mM EGTA, and 1 mM MgSO4) containing 1 mM GTP and 1 mM 2-mercaptoethanol. Tubulin was prepared from the microtubule protein by phosphocellulose chromatography and stored at −70 °C. Tubulin was mixed with indicated concentrations of test compounds (e.g. docetaxel) in PEM buffer (100 mM PIPES, 1mMMgCl2, and 1mMEGTA) containing 1mMGTP and 5% glycerol. Microtubule polymerization was monitored by a spectrophotometer at 340 nm. The plateau absorbance values were used for calculations[5]. | ||
| Cell Assay | The wide use of paclitaxel and docetaxel in NSCLC clinical treatment makes it necessary to find biomarkers for identifying patients who can benefit from paclitaxel or docetaxel. In present study, NCI-H460, a NSCLC cell line with different sensitivity to paclitaxel and docetaxel, was applied to DNA microarray expression profiling analysis at different time points of lower dose treatment with paclitaxel or docetaxel. And the complex signaling pathways regulating the drug response were identified, and several novel sensitivity-realted markers were biocomputated.The dynamic changes of responding genes showed that paclitaxel effect is acute but that of docetaxel is durable at least for 48 hours in NCI-H460 cells. Functional annotation of the genes with altered expression showed that genes/pathways responding to these two drugs were dramatically different. Gene expression changes induced by paclitaxel treatment were mainly enriched in actin cytoskeleton (ACTC1, MYL2 and MYH2), tyrosine-protein kinases (ERRB4, KIT and TIE1) and focal adhesion pathway (MYL2, IGF1 and FLT1), while the expression alterations responding to docetaxel were highly co-related to cell surface receptor linked signal transduction (SHH, DRD5 and ADM2), cytokine-cytokine receptor interaction (IL1A and IL6) and cell cycle regulation (CCNB1, CCNE2 and PCNA). Moreover, we also confirmed some different expression patterns with real time PCR. Our study will provide the potential biomarkers for paclitaxel and docetaxel-selection therapy in clinical application[2]. | ||
| Animal Protocol |
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| ADME/Pharmacokinetics |
Absorption The pharmacokinetic profile of docetaxel is consistent with a three-compartment model. The initial rapid decline represents the distribution to the peripheral compartments, and the late (terminal) phase is partly due to a relatively slow efflux of docetaxel from the peripheral compartment. The area under the curve (AUC) was dose proportional at doses between 70 mg/m2 and 115 mg/m2 with infusion times of 1 to 2 hours. In a group of patients with solid tumors given 100 mg/m2 of docetaxel intravenously, the Cmax and AUC were 2.41 μg/mL and 5.93 μg⋅h/mL, respectively. Route of Elimination Docetaxel was eliminated in urine and feces following oxidative metabolism of the tert-butyl ester group, but fecal excretion was the main elimination route. Within 7 days, urinary and fecal excretion accounted for approximately 6% and 75% of the administered radioactivity, respectively. In the first 48 hours, approximately 80% of the radioactivity recovered was excreted in feces. One major and three minor metabolites were excreted at this point, with less than 8% as the unchanged drug. Volume of Distribution Docetaxel has a steady-state volume of distribution of 113 L. Its pharmacokinetic profile is consistent with a three-compartment pharmacokinetic model. Clearance After the administration of 20–115 mg/m2 of intravenous docetaxel to cancer patients, the total body clearance was 21 L/h/m2. In patients aged 1 to 20 years with solid tumors that received 55 mg/m2 to 235 mg/m2 of docetaxel in a 1-hour intravenous infusion every 3 weeks, clearance was 17.3 L/h/m2. The initial rapid decline represents distribution to the peripheral compartments and the late (terminal) phase is due, in part, to a relatively slow efflux of docetaxel from the peripheral compartment. Mean steady state volume of distribution was 113 L. In vitro studies showed that docetaxel is about 94% protein bound, mainly to alpha1-acid glycoprotein, albumin, and lipoproteins. In three cancer patients, the in vitro binding to plasma proteins was found to be approximately 97%. Dexamethasone does not affect the protein binding of docetaxel. A study of (14)C-docetaxel was conducted in three cancer patients. Docetaxel was eliminated in both the urine and feces following oxidative metabolism of the tert-butyl ester group, but fecal excretion was the main elimination route. Within 7 days, urinary and fecal excretion accounted for approximately 6% and 75% of the administered radioactivity, respectively. About 80% of the radioactivity recovered in feces is excreted during the first 48 hours as 1 major and 3 minor metabolites with very small amounts (less than 8%) of unchanged drug. The pharmacokinetics of docetaxel have been evaluated in cancer patients after administration of 20 mg/m2 to 115 mg/sq m in phase 1 studies. The area under the curve (AUC) was dose proportional following doses of 70 mg/sq m to 115 mg/sq m with infusion times of 1 to 2 hours. Docetaxel's pharmacokinetic profile is consistent with a three-compartment pharmacokinetic model, with half-lives for the alpha, beta, and gamma phases of 4 min, 36 min, and 11.1 hr, respectively. Mean total body clearance was 21 L/hr/sq m. View More
Metabolism / Metabolites Biological Half-Life With plasma sampling up to 8 to 22 days after docetaxel infusion, the terminal elimination half-life was 116 hours. Doses between 70 and 115 mg/m2 with infusion times of 1 to 2 hours produce a triphasic elimination profile. The half-life of the alpha, beta, and gamma phases are 4 minutes, 36 minutes, and 11.1 hours, respectively. |
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| Toxicity/Toxicokinetics |
Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation Most sources consider breastfeeding to be contraindicated during maternal antineoplastic drug therapy. No information is available on the clinical use of docetaxel during breastfeeding. It has been suggested that breastfeeding should be discontinued for 4 to 5 days after a dose, although the manufacturer recommends that breastfeeding be discontinued for 1 week after the last dose. Chemotherapy may adversely affect the normal microbiome and chemical makeup of breastmilk. Women who receive chemotherapy during pregnancy are more likely to have difficulty nursing their infant. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk A telephone follow-up study was conducted on 74 women who received cancer chemotherapy at one center during the second or third trimester of pregnancy to determine if they were successful at breastfeeding postpartum. Only 34% of the women were able to exclusively breastfeed their infants, and 66% of the women reported experiencing breastfeeding difficulties. This was in comparison to a 91% breastfeeding success rate in 22 other mothers diagnosed during pregnancy, but not treated with chemotherapy. Other statistically significant correlations included: (1) mothers with breastfeeding difficulties had an average of 5.5 cycles of chemotherapy compared with 3.8 cycles among mothers who had no difficulties; and (2) mothers with breastfeeding difficulties received their first cycle of chemotherapy on average 3.4 weeks earlier in pregnancy. Of the 9 women who received a taxane-containing regimen, 7 had breastfeeding difficulties. |
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| References |
[1]. The chemomodulatory effects of glufosfamide on docetaxel cytotoxicity in prostate cancer cells. PeerJ. 2016 Jun 29;4:e2168. [2]. DNA microarray reveals different pathways responding to paclitaxel and docetaxel in non-small cell lung cancer cell line. Int J Clin Exp Pathol. 2013 Jul 15;6(8):1538-48. [3]. Involvement of Wee1 in the circadian rhythm dependent intestinal damage induced by docetaxel. J Pharmacol Exp Ther. 2013 Oct;347(1):242-8. [4]. Non-linear pharmacokinetics of piperine and its herb-drug interactions with docetaxel in Sprague-Dawley rats. J Pharm Biomed Anal. 2016 Sep 5;128:286-93. |
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| Additional Infomation |
Docetaxel trihydrate is the trihydrate form of docetaxel. It is used for the treatment of breast, ovarian, and non-small cell lung cancer, and with prednisone or prednisolone in hormone-refractory metastatic prostate cancer. It has a role as an antineoplastic agent. It is a hydrate and a secondary alpha-hydroxy ketone. It contains a member of docetaxel anhydrous. Docetaxel is a semi-synthetic, second-generation taxane derived from a compound found in the European yew tree, Taxus baccata. Docetaxel displays potent and broad antineoplastic properties; it binds to and stabilizes tubulin, thereby inhibiting microtubule disassembly which results in cell- cycle arrest at the G2/M phase and cell death. This agent also inhibits pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and displays immunomodulatory and pro-inflammatory properties by inducing various mediators of the inflammatory response. Docetaxel has been studied for use as a radiation-sensitizing agent. (NCI04) A semisynthetic analog of PACLITAXEL used in the treatment of locally advanced or metastatic BREAST NEOPLASMS and NON-SMALL CELL LUNG CANCER. See also: Docetaxel (annotation moved to). Drug Indication Breast cancer Taxespira in combination with doxorubicin and cyclophosphamide is indicated for the adjuvant treatment of patients with: operable node-positive breast cancer ; operable node-negative breast cancer . For patients with operable node-negative breast cancer , adjuvant treatment should be restricted to patients eligible to receive chemotherapy according to internationally established criteria for primary therapy of early breast cancer . Taxespira in combination with doxorubicin is indicated for the treatment of patients with locally advanced or metastatic breast cancer who have not previously received cytotoxic therapy for this condition. Taxespira monotherapy is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic therapy. Previous chemotherapy should have included an anthracycline or an alkylating agent. Taxespira combination with trastuzumab is indicated for the treatment of patients with metastatic breast cancer whose tumours over express HER2 and who previously have not received chemotherapy for metastatic disease. Taxespira in combination with capecitabine is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy. Previous therapy should have included an anthracycline. Non-small cell lung cancer Taxespira indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of prior chemotherapy. Taxespira in combination with cisplatin is indicated for the treatment of patients with unresectable, locally advanced or metastatic non-small cell lung cancer , in patients who have not previously received chemotherapy for this condition. Prostate cancer Taxespira in combination with prednisone or prednisolone is indicated for the treatment of patients with hormone refractory metastatic prostate cancer . Gastric adenocarcinoma Taxespira in combination with cisplatin and 5-fluorouracil is indicated for the treatment of patients with metastatic gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who have not received prior chemotherapy for metastatic disease. Head and neck cancer Taxespira in combination with cisplatin and 5-fluorouracil is indicated for the induction treatment of patients with locally advanced squamous cell carcinoma of the head and neck. |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (2.90 mM) (saturation unknown) in 10% EtOH + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear EtOH stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (2.90 mM) (saturation unknown) in 10% EtOH + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear EtOH stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. 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. Solubility in Formulation 3: ≥ 2.5 mg/mL (2.90 mM) (saturation unknown) in 10% EtOH + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear EtOH stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 4: ≥ 2.08 mg/mL (2.41 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 5: ≥ 2.08 mg/mL (2.41 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. 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. Solubility in Formulation 6: ≥ 2.08 mg/mL (2.41 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.1602 mL | 5.8009 mL | 11.6019 mL | |
| 5 mM | 0.2320 mL | 1.1602 mL | 2.3204 mL | |
| 10 mM | 0.1160 mL | 0.5801 mL | 1.1602 mL |