HuagongsheHuagongshe Chemie-Druckbericht · Nur für Forschungszwecke
Topotecan
HYDROCHLORIDE · 3-[1-methyl-6-(4-piperidyl)indazol-3-yl]piperidine-2,6-dione · Hycamtin · TOPOTECAN HCL · 3-amino-1,3-dimethyl-cyclobutanol · 2-(3-Chloro-5-trifluoromethyl-pyridin-2-yl)-ethylamine · (1R)-6,7-dimethoxy-1-[(4-methoxyphenyl)methyl]-1,2,3,4-tetrahydroisoquinoline · 108563
Identifikatoren & physikalische Daten
| CAS No. | 119413-54-6 |
|---|---|
| Summenformel | C23H23N3O5 |
| Durchschnittliche Molmasse | 421,4 g/mol |
| Monoisotopische Masse | 421,16377084 g/mol |
| SMILES | CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3c(CN(C)C)c(O)ccc3nc2-1 |
| InChIKey | UCFGDBYHRUNTLO-QHCPKHFHSA-N |
| PubChem CID | 60700 |
| ChEMBL | CHEMBL84 |
| ChEBI | CHEBI:63632 |
| EC No. | 687-471-1 |
| DTXSID | DTXSID3042685 |
Chemische & physikalische Eigenschaften
| XLogP | 0,5 |
|---|---|
| Polarare Oberfläche (TPSA) | 103 |
| H-Brücken-Donoren | 2 |
| H-Brücken-Akzeptoren | 7 |
| Frei drehbare Bindungen | 3 |
| Schwere Atome | 31 |
| Formalladung | 0 |
| Komplexität | 867 |
| Arzneimittel | Pharmaceuticals -> Listed in ZINC15 |
| LogP (Verteilungskoeffizient) | 0.80.91 |
| Löslichkeit | 8.61e-01 g/LDMSO (Slightly), Methanol (Slightly), Water (Slightly) |
| Human Drugs | Breast FeedingLactationAntineoplastic AgentsTopoisomerase I InhibitorsEMA approved medicines: Human medicine |
| Decomposition | Hazardous decomposition products: Hazardous decomposition products formed under fire conditions. - Carbon oxides, nitrogen oxides (NOx), hydrogen chloride gas. |
| Schmelzpunkt | 213-218 °C213 - 218 °C213-218°C |
| Physical Description | Solid |
| Stability/Shelf Life | Stable under recommended storage conditions. |
| Collision Cross Section | 223.05 Ų [M+Na]+ [CCS Type: TWMethod: calibrated with polyalanine and drug standards] |
| Other Experimental Properties | Light yellow to greenish powder, mp 213-218 °C (decomposes). Soluble in water up to 1 mg/mL. Hygroscopic. Heant and light sensitive /Topotecan hydrochloride/ |
| Lagerbedingungen | Sealed in dry,Room Temperature |
| Aggregatzustand | Light yellow to greenish powder. |
| Farbe | White to Off-White |
| Stabilität | Hygroscopic |
| InChIKey | DGHHQBMTXTWTJV-UUTVKYGWNA-N |
| SMILES | C12C=C3N(CC4C=C5C(CN(C)C)=C(O)C=CC5=NC3=4)C(=O)C=1COC(=O)[C@]2(O)CC.Cl |&1:27,r| |
| CAS Datenbank | 119413-54-6(CAS DataBase Reference) |
Sicherheit & Vorschriften
| GHS-Einstufung | DangerH301 (18.8%): Toxic if swallowed [Danger Acute toxicity, oral]P203, P261, P264, P264+P265, P270, P271, P280, P301+P316, P302+P352, P304+P340, P305+P351+P338, P318, P319, P321, P330, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)Aggregated GHS information provided per 48 reports by companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.WarningH341: Suspected of causing genetic defects [Warning Germ cell mutagenicity] |
|---|---|
| FDA-Anforderungen | The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including topotecan hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Topotecan hydrochloride/ |
| Hazard Classes and Categories | Acute Tox. 3 (18.8%) |
| Hazardous Reactivities and Incompatibilities | Incompatible materials: Strong oxidizing agents. |
| Brandbekämpfungsverfahren | Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.Advice for firefighters: Wear self contained breathing apparatus for fire fighting if necessary. |
| Lagerbedingungen | Store the vials protected from light in the original cartons at controlled room temperature between 20 deg and 25 °C (68 deg and 77 °F).Conditions for safe storage, including any incompatibilities: Keep container tightly closed in a dry and well-ventilated place. Recommended storage temperature: -20 °C. |
| Reinigungsverfahren | Accidental Release Measures. Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapours, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal. |
| Entsorgungsverfahren | SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.Waste treatment methods. Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber. Contaminated packaging: Dispose of as unused product. |
| Preventive Measures | Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed.Appropriate engineering controls: Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday.Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker. |
| Personal Protective Equipment (PPE) | Eye/face protection: Safety glasses with side-shields conforming to EN166 Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).Skin protection: Handle with gloves.Body Protection: Impervious clothing. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.Respiratory protection: Where risk assessment shows air-purifying respirators are appropriate use a full-face particle respirator type N100 (US) or type P3 (EN 143) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). |
| Wechselwirkungen | Topotecan is a substrate of the efflux transporters P-glycoprotein (Pgp, ABCB1) and ABCG2 (breast cancer resistance protein (BRCP)). Concomitant use of elacridar (not commercially available in the US), an inhibitor of both P-glycoprotein and ABCG2 transporters, with oral topotecan resulted in a 2.5-fold increase in the area under the plasma concentration-time curve (AUC) for both topotecan lactone, the pharmcologically active form of the drug, and total topotecan. Concomitant use of oral topotecan with inhibitors of P-glycoprotein (e.g., cyclosporine, ketoconazole, ritonavir, saquinavir) also resulted in substantial increases in topotecan exposure. In one study, concomitant use of cyclosporine administered within 4 hours of an oral dose of topotecan resulted in a 2- to 3-fold increase in the AUCs of both topotecan lactone and total topotecan. The manufacturer states that concomitant use of oral topotecan with Pgp inhibitors should be avoided. If topotecan is used concomitantly with a Pgp (ABCB1) and/or an ABCG2 inhibitor, careful monitoring for signs of toxicity should be performed.Topotecan (TpT) is a major inhibitory compound of topoisomerase (topo) I that plays important roles in gene transcription and cell division. We have previously reported that heparin and heparan sulfate (HS) might be transported to the cell nucleus and they can interact with topoisomerase I. We hypothesized that heparin and HS might interfere with the action of TpT. To test this hypothesis we isolated topoisomerase I containing cell nuclear protein fractions from normal liver, liver cancer tissues, and hepatoma cell lines. The enzymatic activity of these extracts was measured in the presence of heparin, liver HS, and liver cancer HS. In addition, topo I activity, cell viability, and apoptosis of HepG2 and Hep3B cells were investigated after heparin and TpT treatments. Liver cancer HS inhibited topo I activity in vitro. Heparin treatment abrogated topo I enzyme activity in Hep3B cells, but not in HepG2 cells, where the basal activity was higher. Heparin protected the two hepatoma cell lines from TpT actions and decreased the rate of TpT induced S phase block and cell death. These results suggest that heparin and HS might interfere with the function of TpT in liver and liver cancer.The severity of drug-induced myelosuppression may be increased when IV topotecan is used in combination with other cytotoxic agents, and dosage reduction may be necessary. Severe myelotoxicity, in some cases resulting in fatalities from sepsis, has occurred during combined therapy with IV topotecan and other antineoplastic agents (e.g., cisplatin, paclitaxel). A sequence-dependent interaction has been reported when IV topotecan is administered concomitantly with cisplatinlower doses of each drug were required with administration of cisplatin on day 1 of the topotecan dosing schedule compared with administration of cisplatin on day 5 of the topotecan dosing schedule.Concurrent administration of granulocyte colony-stimulating factor (G-CSF) can prolong the duration of neutropenia associated with IV topotecan therapy. If G-CSF (filgrastim) is to be used concomitantly, therapy should be initiated 24 hours after the final dose of IV topotecan (i.e., beginning on day 6 of the 21-day treatment course for monotherapy or beginning on day 4 of the 21-day treatment course for combination therapy with IV topotecan and cisplatin). |
| Milk Concentrations | EXPERIMENTAL: In lactating rats receiving IV topotecan at a dosage of 4.72 mg/sq m, high concentrations of the drug (i.e., up to 48 times higher than plasma concentrations) were distributed into milk. It is not known whether topotecan is distributed into human milk. |
| Toxizitätsübersicht | IDENTIFICATION AND USE: Topotecan is antineoplastic medication acting as topoisomerase I inhibitor. HUMAN EXPOSURE AND TOXICITY: The dose-limiting toxicity of topotecan is leukopenia. Topotecan-induced neutropenia can cause neutropenic colitis. Fatalities due to neutropenic colitis have been reported in clinical trials with topotecan. Overdoses (up to 10-fold of the prescribed dose) occurred in patients treated with intravenous topotecan. The primary complication of overdosage is bone marrow suppression. Interstitial lung disease (sometimes fatal) has been reported during postmarketing experience with IV topotecan. Risk factors for developing interstitial lung disease include pulmonary fibrosis, lung cancer, exposure to thoracic radiation, use of drugs known to cause pulmonary toxicity, use of colony-stimulating factors (i.e., hematopoietic growth factors), and a history of interstitial lung disease. Patients should be monitored for symptoms suggestive of interstitial lung disease, including cough, fever, dyspnea, and/or hypoxia. Case report describes a patient with pre-existing pulmonary fibrosis and progressive extensive stage small cell lung cancer. After receiving a single intravenous dose of topotecan, the patient developed sub-acute respiratory failure, and died 15 days later with pathology findings of organizing, reparative phase, diffuse alveolar damage. Topotecan was clastogenic to cultured human lymphocytes with and without metabolic activation. ANIMAL STUDIES: Single dose toxicity was investigated in rodents and dogs following intravenous administration of topotecan. Doses of 56, 148 or 74 mg/ sq m were lethal in mice, rats or dogs respectively. Target organs of toxicity were bone marrow, lymphoid tissues, gastrointestinal tract and ovaries. In repeat dose experiments at or below the maximum tolerated dose, the toxicity profile was characterized by myelotoxicity (neutropenia, thrombocytopenia, lymphopenia and anemia), lymphoid depletion and gastrointestinal effects. Furthermore, other tissues with a rapid cell turnover, such as hair follicles and testis were affected. The main dose-limiting toxicity was the effect on bone marrow. In surviving animals, effects were reversible after termination of treatment. In mice, a single treatment with a cytotoxic agent causes cognitive impairment. Studies in dogs given about 1/4th the clinical dose of the drug daily for a month suggest that treatment may cause an increase in the incidence of multinucleated spermatogonial giant cells in the testes. Topotecan given to female rats prior to mating at a dose equal to the clinical dose caused superovulation possibly related to inhibition of follicular atresia. This dose given to pregnant female rats also caused increased pre-implantation loss. Topotecan was mutagenic to L5178Y mouse lymphoma cells with and without metabolic activation. It was also clastogenic to mouse bone marrow. Topotecan did not cause mutations in bacterial cells. Topotecan is also a germ cell mutagen and its effect is more pronounced during the post-meiotic stages through a mechanism that may involve increases in DNA oxidative stress. |
| Natural Pollution Sources | Topotecan is manufactured from Camptothecin, a natural plant substance found in Camptothecin acuminata (Family: Nyssaceae) and Nothapodytes nimmoniana (Synonym: Mappia foetida, Family: Icacinaceae)(1,2). |
| Human Toxicity Excerpts | /SIGNS AND SYMPTOMS/ Topotecan-induced neutropenia can cause neutropenic colitis (cecitis or typhlitis). Fatalities due to neutropenic colitis have been reported in clinical trials with topotecan. In patients presenting with fever, neutropenia, and a compatible pattern of abdominal pain, the possibility of neutropenic colitis should be considered./SIGNS AND SYMPTOMS/ Overdoses (up to 10-fold of the prescribed dose) occurred in patients treated with intravenous topotecan. The primary complication of overdosage is bone marrow suppression. The observed signs and symptoms of overdose are consistent with the known adverse reactions associated with Hycamtin for intravenous use. In addition, elevated hepatic enzymes and mucositis have been reported following overdose./SIGNS AND SYMPTOMS/ Interstitial lung disease (sometimes fatal) has been reported during postmarketing experience with IV topotecan. Risk factors for developing interstitial lung disease include pulmonary fibrosis, lung cancer, exposure to thoracic radiation, use of drugs known to cause pulmonary toxicity, use of colony-stimulating factors (i.e., hematopoietic growth factors), and a history of interstitial lung disease. Patients should be monitored for symptoms suggestive of interstitial lung disease, including cough, fever, dyspnea, and/or hypoxia. If a new diagnosis of interstitial lung disease is confirmed, the manufacturer states that topotecan therapy should be discontinued./CASE REPORTS/ Drug-induced pulmonary toxicities of anticancer agents have been well described, but the pathophysiology of agents typically used in advanced disease has not been well studied. Symptoms of pulmonary drug toxicity in advanced lung cancer patients may frequently be attributed to disease progression, pulmonary embolism, or infection. In patients with pre-existing interstitial pulmonary fibrosis even less is known. This report describes an unfortunate patient with pre-existing pulmonary fibrosis and progressive extensive stage small cell lung cancer. After receiving a single intravenous dose of topotecan, the patient developed sub-acute respiratory failure, and died 15 days later with pathology findings of organizing, reparative phase, diffuse alveolar damage. To our knowledge this is the first pathology confirmation of diffuse alveolar damage in a patient developing dyspnea following topotecan therapy. The frequency with which camptothecin-related dyspnea is associated with diffuse alveolar damage might be underestimated and is of special concern in patients with limited pulmonary reserve.For more Human Toxicity Excerpts (Complete) data for Topotecan (6 total), please visit the HSDB record page. |
| Drug Induced Liver Injury | Drug-Induced Liver Injury Severity and Toxicity (DILIst)topotecanDILI NegativeOralDOI:10.1016/j.drudis.2019.09.022 |
| Non-Human Toxicity Excerpts | /LABORATORY ANIMALS: Acute Exposure/ Single dose toxicity was investigated in rodents and dogs following intravenous administration of topotecan. Doses of 56, 148 or 74 mg/sq m were lethal in mice, rats or dogs respectively. Target organs of toxicity were bone marrow, lymphoid tissues, gastrointestinal tract and ovaries./LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Repeat dose toxicity following intravenous administration of topotecan was studied in mice (5 days study), as well as in rats and dogs (5-28 days studies). In addition, rats were administered topotecan by the oral route during 6 months. All species showed signs of toxicity consistent with the pharmacological effects of topotecan. At or below the maximum tolerated dose (MTD, being 4.7 mg/sq m/day in rats and 1.3 mg/sq m/day in dogs), the toxicity profile was characterised by myelotoxicity (neutropenia, thrombocytopenia, lymphopenia and anemia), lymphoid depletion and gastrointestinal effects. Furthermore, other tissues with a rapid cell turnover, such as hair follicles and testis were affected. The main dose-limiting toxicity was the effect on bone marrow. In surviving animals, effects were reversible after termination of treatment. The available animal data do not indicate a potential for toxicity in major organs other than expected./LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Studies in dogs given 0.4 mg/sq m IV (about 1/4th the clinical dose on a mg/sq m basis) of topotecan daily for a month suggest that treatment may cause an increase in the incidence of multinucleated spermatogonial giant cells in the testes./LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Topotecan given to female rats prior to mating at a dose of 1.4 mg/sq m IV (about equal to the clinical dose on a mg/sq m basis) caused superovulation possibly related to inhibition of follicular atresia. This dose given to pregnant female rats also caused increased pre-implantation loss.For more Non-Human Toxicity Excerpts (Complete) data for Topotecan (7 total), please visit the HSDB record page. |
| Populations at Special Risk | Because elimination of oral and IV topotecan may be prolonged in patients with renal impairment and geriatric patients may have decreased renal function, the risk of adverse effects may be greater in such patients. Careful dosage selection and monitoring of renal function are advised in geriatric patients receiving topotecan.... In patients with pre-existing interstitial pulmonary fibrosis even less is known. This report describes an unfortunate patient with pre-existing pulmonary fibrosis and progressive extensive stage small cell lung cancer. After receiving a single intravenous dose of topotecan, the patient developed sub-acute respiratory failure, and died 15 days later with pathology findings of organizing, reparative phase, diffuse alveolar damage. To our knowledge this is the first pathology confirmation of diffuse alveolar damage in a patient developing dyspnea following topotecan therapy. The frequency with which camptothecin-related dyspnea is associated with diffuse alveolar damage might be underestimated and is of special concern in patients with limited pulmonary reserve.Topotecan can cause fetal toxicity when administered to pregnant women. If the drug is administered during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus. The manufacturer states that use of oral topotecan is contraindicated in pregnant and nursing women.Hycamtin is contraindicated in patients who have a history of severe hypersensitivity reactions (e.g., anaphylactoid reactions) to topotecan or to any of its ingredients. Hycamtin should not be used in patients with severe bone marrow depression.Myelosuppression, principally neutropenia, is the dose-limiting toxicity of topotecan, and use of the drug is contraindicated in patients with severe myelosuppression. Oral and IV topotecan therapy should not be initiated in patients with baseline neutrophil counts less than 1500/cu mm or platelet counts less than 100,000/cu mm. |
| Antidote and Emergency Treatment | Emergency and supportive measures. 1. Maintain an open airway and assist ventilation if necessary. 2. Treat coma, seizures, hypotension, and arrhythmias if they occur. 3. Treat nausea and vomiting with ondansetron or metoclopramide. Consider adding a benzodiazepine. Treat fluid losses caused by gastroenteritis with IV crystalloid fluids. 4. Bone marrow depression should be treated with the assistance of an experienced hematologist or oncologist. Transfusions of packed red blood cells and platelets may be needed for episodes of bleeding. Recombinant erythropoietin may be useful for severe anemia, and hematopoietic colony-stimulating factors may be useful for neutropenia. ... /Antineoplastics/Decontamination. Administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly. /Antineoplastics/Enhanced elimination. Because of the rapid intracellular incorporation of most of these agents, dialysis and other extracorporeal removal procedures are generally not effective ... . /Antineoplastic//SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/For more Antidote and Emergency Treatment (Complete) data for Topotecan (6 total), please visit the HSDB record page. |
| Effects During Pregnancy and Lactation | ◉ Summary of Use during Lactation |
| Non-Human Toxicity Values | LD50 Mouse iv 74.85 mg/sq m (CI 95%: 47.22 to 97.41) |
| Zollcode | 29420000 |
| R-Sätze (R) | 25-36/37/38-46 |
| Gefahrensymbole | T |
| Sicherheitshinweise (S) | 26-36/37/39-45 |
Anwendungen & Verwendung
Verwenden
A DNA topoisomerase I inhibitor; semisynthetic analog of Camptothecin. Antineoplastic. Topotecan hydrochloride is a chemotherapy agent that is a topoisomerase 1 inhibitor.