Quetiapine

QUETIAPIN · Quetiapine Base · 10-diol · uetiapine · Ketipinor · Quetiapine · Quetiapize · omega-Decanediol

Identifikatoren & physikalische Daten

CAS No.	111974-69-7
Summenformel	C21H25N3O2S
Durchschnittliche Molmasse	383,5 g/mol
Monoisotopische Masse	383,16674804 g/mol
SMILES	OCCOCCN1CCN(C2=Nc3ccccc3Sc3ccccc32)CC1
InChIKey	URKOMYMAXPYINW-UHFFFAOYSA-N
PubChem CID	5002
ChEMBL	CHEMBL716
ChEBI	CHEBI:8707
EC No.	601-143-7
DTXSID	DTXSID9023546

Chemische & physikalische Eigenschaften

XLogP	2,1
Polarare Oberfläche (TPSA)	73,6
H-Brücken-Donoren	1
H-Brücken-Akzeptoren	5
Frei drehbare Bindungen	6
Schwere Atome	27
Formalladung	0
Komplexität	496
Arzneimittel	Pharmaceuticals -> Listed in ZINC15Pharmaceuticals -> Used in SwitzerlandPharmaceuticals -> Antipsychotics
LogP (Verteilungskoeffizient)	3.54
Color/Form	Solid
Löslichkeit	49.4 [ug/mL] (The mean of the results at pH 7.4)H2O : < 0.1 mg/mL (insoluble)
Flammpunkt	9.7 °C (49.5 °F) - closed cup
Human Drugs	Breast FeedingLactationMilk, HumanAntipsychotic AgentsMedicines for bipolar disorders
Siedepunkt	556.5±60.0556.5±60.0 °C(Predicted)
Schmelzpunkt	174-176172-173 °C
Physical Description	Solid
Stability/Shelf Life	Stable under recommended storage conditions.
Dissociation Constants	7.06
Collision Cross Section	188.6 Å² [M+Na]+ [CCS Type: DTBuffer gas: N2Ionization: ESI+Dataset: TOXCASTSource Identifier: DTXSID3044201]192.9 Å² [M+H]+ [CCS Type: TWMethod: Major Mix IMS/Tof Calibration Kit (Waters)]190.58 Å² [M+K]+ [CCS Type: TWMethod: calibrated with polyalanine and drug standards]191.1 Å² [M+H]+ [CCS Type: DTMethod: single field calibrated]191.5 Å² [M+H]+ [CCS Type: TW
Dichte	1.27±0.1 g/cm3(Predicted)
Lagerbedingungen	Store at -20°C
Aggregatzustand	Powder
pKa (Säurekonstante)	14.41±0.10(Predicted)
Farbe	Light yellow to yellow
Stabilität	Very Hygroscopic
LogP (Verteilungskoeffizient)	0.899
CAS Datenbank	111974-69-7(CAS DataBase Reference)

Sicherheit & Vorschriften

GHS-Einstufung	DangerH302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]P261, P264, P264+P265, P270, P271, P273, P280, P301+P317, P304+P340, P305+P354+P338, P317, P319, P330, P391, P403+P233, P405, and P501 (click each P-code to see the statement)Aggregated GHS information provided per 4 reports by companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.H225: Highly Flammable liquid and vapor [Danger Flammable liquids]
Regulatorische Informationen	Status: Active Update: 11-04-2022 https://echa.europa.eu/registration-dossier/-/registered-dossier/33496
FDA-Anforderungen	The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including quetiapine fumarate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Quetiapine fumarate/
Hazard Classes and Categories	Acute Tox. 4 (100%)
Hazardous Reactivities and Incompatibilities	Incompatible materials: Acids, Oxidizing agents, Alkali metals, Strong oxidizing agents, Strong acids, Acid chlorides, Acid anhydrides, Reducing agents, Strong reducing agents, Phosphorus halides
Brandbekämpfungsverfahren	Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary. Use water spray to cool unopened containers.Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.
Lagerbedingungen	Conditions for safe storage, including any incompatibilities: Keep container tightly closed in a dry and well-ventilated place. Containers which are opened must be carefully resealed and kept upright to prevent leakage. Recommended storage temperature -20 °C
Reinigungsverfahren	ACCIDENTAL RELEASE MEASURES. Personal precautions, protective equipment and emergency procedures: Wear respiratory protection. Avoid breathing vapours, mist or gas. Ensure adequate ventilation. Remove all sources of ignition. Evacuate personnel to safe areas. Beware of vapours accumulating to form explosive concentrations. Vapours can accumulate in low areas.Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Discharge into the environment must be avoided.Methods and materials for containment and cleaning up: Contain spillage, and then collect with an electrically protected vacuum cleaner or by wet-brushing and place in container for disposal according to local regulations.
Entsorgungsverfahren	SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.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.
Preventive Measures	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.Appropriate engineering controls: Avoid contact with skin, eyes and clothing. Wash hands before breaks and immediately after handling the product.Precautions for safe handling: Avoid contact with skin and eyes. Avoid inhalation of vapour or mist. Use explosion-proof equipment.Keep away from sources of ignition - No smoking.Take measures to prevent the build up of electrostatic charge.
Personal Protective Equipment (PPE)	Respiratory protection: Where risk assessment shows air-purifying respirators are appropriate use a full-face respirator with multipurpose combination (US) or type ABEK (EN 14387) 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).Body Protection: Complete suit protecting against chemicals, Flame retardant antistatic protective clothing., The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.Skin protection: Handle with gloves.Eye/face protection: Face shield and safety glasses Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).
Körperbelastung	... The quetiapine mean and range of concentrations found in each tissue are as follows: peripheral blood, 7.7 mg/L (0.14-37 mg/L, n = 17)heart blood, 23.63 mg/L (0.53-76 mg/L, n = 4)liver, 91 mg/Kg (1.1-510 mg/Kg, n = 19)bile, 44 mg/L (6.0-96 mg/L, n = 4)urine, 15 mg/L (1.9-37 mg/L, n = 8)gastric, 897 mg total (3.5-3960 mg, n = 7)and vitreous, 1.4 mg/L (0.2-3.2 mg/L, n = 5). The average of all blood concentrations in 18 cases in which quetiapine contributed to the cause of death was 7.95 mg/L (0.4-76 mg/L). The manner of death in 13 of those cases was suicide, two were undetermined, and three were accidents. In two cases in which quetiapine was an incidental finding, the blood concentrations were 0.14 and 1.0 mg/L. ...
Treatment	There is no specific antidote. Treat quinidine-like cardiotoxic effects with bicarbonate. Maintain an open airway and assist ventilation if necessary. Administer supplemental oxygen. (L304)
Wechselwirkungen	Coadministration of quetiapine (250 mg) and phenytoin (100 mg) increased the mean oral clearance of quetiapine by 5-fold. Increased doses of quetiapine may be required to maintain control of symptoms of schizophrenia in patients receiving quetiapine and phenytoin, or other hepatic enzyme inducers (e.g., carbamazepine, barbiturates, rifampin, glucocorticoids). Caution should be taken if phenytoin is withdrawn and replaced with a non-inducer (e.g., valproate)Coadministration of quetiapine (150 mg) and divalproex (500 mg) increased the mean maximum plasma concentration of quetiapine at steady state by 17% without affecting the extent of absorption or mean oral clearance.Thioridazine (200 mg) increased the oral clearance of quetiapine (300 mg) by 65%.Administration of multiple daily doses of cimetidine (400 mg) resulted in a 20% decrease in the mean oral clearance of quetiapine (150 mg).For more Interactions (Complete) data for QUETIAPINE (10 total), please visit the HSDB record page.
Gesundheitliche Auswirkungen	Tachycardia, development of tardive dyskinesia, an incurable neurological disorder, and a neuroleptic malignant syndrome may result from use or overdose of Quetiapine (L1125).
Hepatotoxicity	Liver test abnormalities may occur in up to 30% of patients on long term therapy with quetiapine, but elevations are uncommonly above 3 times the upper limit of normal. The aminotransferase abnormalities are usually mild, asymptomatic and transient, reversing even with continuation of medication. Instances of clinically apparent acute liver injury have been reported due to quetiapine, but they are rare. The onset of jaundice is within 1 to 4 weeks of starting the drug, and the pattern of serum enzyme elevations is typically hepatocellular. Signs of immunoallergic manifestations (fever, rash and eosinophilia) are rare, as are autoantibodies. Most cases are mild-to-moderate in severity and self-limited in course. Instances of DRESS syndrome and acute liver failure have been reported but not vanishing bile duct syndrome or chronic liver injury.
Umweltverhalten	TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 3.2X10+4(SRC), determined from a structure estimation method(2), indicates that quetiapine is expected to be immobile in soil(SRC). The estimated pKa values of quetiapine are 2.78 and 7.46(3), indicating that this compound will exist partially in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization of quetiapine from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 7.5X10-18 atm-cu m/mole(SRC), using a fragment constant estimation method(5). Quetiapine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 5.4X10-14 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2015).AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 3.2X10+4(SRC), determined from a structure estimation method(2), indicates that quetiapine is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 7.5X10-18 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 31(SRC), from an estimated log Kow of 3.17(2) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is moderate(SRC). Biodegradation data in water were not available(SRC, 2015).ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), quetiapine, which has an estimated vapor pressure of 5.4X10-14 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase quetiapine may be removed from the air by wet and dry deposition(SRC). Quetiapine contains chromophores that absorb at wavelengths >290 nm(4) and, therefore, may to be susceptible to direct photolysis by sunlight(SRC).
Unerwünschte Wirkungen	As with any antipsychotic drug, quetiapine is associated with an increased risk of death in dementia-related psychosis in elderly patients. Alongside this risk, neuroleptic malignant syndrome should be a consideration due to its D2 receptor blockage. It is the least likely of atypical antipsychotics to cause extrapyramidal symptoms. There is an increased risk for suicidal thoughts and behavior associated with drug treatment in major depressive disorder patients. Somnolence, orthostatic hypotension, and dizziness are the most common side effects of quetiapine. Somnolence and dizziness are due to the nature of quetiapine’s antagonism of H1 receptors, while antagonism causes hypotension for alpha-1 receptors. Stroke, myocarditis, and coronary heart disease have also correlated with the use of this drug.
Expositionspfade	Inhalation (MSDS, A308)ingestion (MSDS, A308)dermal (MSDS, A308) Rapidly and well absorbed.
Milk Concentrations	Quetiapine appears to be distributed into milk in humans in relatively small amounts.EXPERIMENTAL: Quetiapine is distributed into milk in animals. Not known whether quetiapine is distributed into milk in humans.
Toxizitätsübersicht	IDENTIFICATION AND USE: Quetiapine fumarate is used for the symptomatic management of psychotic disorders. Short-term efficacy of quetiapine for the management of schizophrenia has been established by placebo-controlled studies of 6 weeks' duration principally in hospitalized patients with schizophrenia. Quetiapine is used alone or in conjunction with lithium or divalproex sodium for the management of acute manic episodes associated with bipolar I disorder. Quetiapine also is used for the treatment of depressive episodes associated with bipolar disorder. HUMAN EXPOSURE AND TOXICITY: The most common adverse effects reported in 5% or more of patients receiving quetiapine therapy for schizophrenia or bipolar disorder and at a frequency twice that reported among patients receiving placebo in clinical trials include somnolence, sedation, asthenia, lethargy, dizziness, dry mouth, constipation, increased ALT, weight gain, dyspepsia, abdominal pain, postural hypotension, and pharyngitis. The development of cataracts in association with quetiapine was observed in animal studies. Lens changes also have been reported in some patients receiving long-term quetiapine therapy, although a causal relationship has not been established. Seizures occurred in 0.6% of patients receiving quetiapine in controlled clinical trials. Geriatric patients with dementia-related psychosis treated with atypical antipsychotic drugs appear to be at an increased risk of death compared with that among patients receiving placebo. Worsening of depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior may occur in both adult and pediatric patients with major depressive disorder and other psychiatric disorders, whether or not they are taking antidepressants. Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome requiring immediate discontinuance of the drug and intensive symptomatic treatment, has been reported in patients receiving antipsychotic agents, including quetiapine. Contact dermatitis, maculopapular rash, and photosensitivity reactions were reported infrequently during clinical trials. Anaphylaxis and Stevens-Johnson syndrome have been reported during postmarketing surveillance. Quetiapine appears to be distributed into human milk in relatively small amounts. The effect of quetiapine on labor and delivery is unknown. Safety and efficacy of quetiapine in pediatric patients younger than 18 years of age with bipolar depression have not been established. Quetiapine overdose causes central nervous system depression and sinus tachycardia. In large overdoses, patients may require intubation and ventilation for associated respiratory depression. Although a prolonged QTc occurs, its clinical significance is unclear because it is most likely caused by an overcorrection caused by the tachycardia. No evidence of clastogenic potential was obtained in an in vitro chromosomal aberration assay in cultured human lymphocytes. ANIMAL STUDIES: Quetiapine caused a dose-related increase in pigment deposition in thyroid gland in a mouse 2 year carcinogenicity study. Doses were 75-750 mg/kg. The identity of the pigment could not be determined, but was found to be co-localized with quetiapine in thyroid gland follicular epithelial cells. The functional effects and the relevance of this finding to human risk are unknown. In dogs receiving quetiapine for 6 or 12 months, but not for 1 month, focal triangular cataracts occurred at the junction of posterior sutures in the outer cortex of the lens at a dose of 100 mg/kg. This finding may be due to inhibition of cholesterol biosynthesis by quetiapine. Quetiapine caused a dose related reduction in plasma cholesterol levels in repeat-dose dog and monkey studieshowever, there was no correlation between plasma cholesterol and the presence of cataracts in individual dogs. The appearance of delta-8-cholestanol in plasma is consistent with inhibition of a late stage in cholesterol biosynthesis in these species. There also was a 25% reduction in cholesterol content of the outer cortex of the lens observed in a special study in quetiapine treated female dogs. The teratogenic potential of quetiapine was studied in rats and rabbits dosed during the period of organogenesis. No evidence of a teratogenic effect was detected in rats at doses of 25 to 200 mg/kg or in rabbits at 25 to 100 mg/kg. There was, however, evidence of embryo/fetal toxicity. Delays in skeletal ossification were detected in rat fetuses at doses of 50 and 200 mg/ kg and in rabbits at 50 and 100 mg/kg. Fetal body weight was reduced in rat fetuses at 200 mg/kg and rabbit fetuses at 100 mg/kg. There was an increased incidence of a minor soft tissue anomaly (carpal/tarsal flexure) in rabbit fetuses at a dose of 100 mg/kg. Evidence of maternal toxicity (i.e., decreases in body weight gain and/or death) was observed at the high dose in the rat study and at all doses in the rabbit study. In a peri/ postnatal reproductive study in rats, no drug-related effects were observed at doses of 1, 10, and 20 mg/kg. However, in a preliminary peri/postnatal study, there were increases in fetal and pup death, and decreases in mean litter weight at 150 mg/kg. The mutagenic potential of quetiapine was tested in six in vitro bacterial gene mutation assays and in an in vitro mammalian gene mutation assay in Chinese Hamster Ovary cells. However, sufficiently high concentrations of quetiapine may not have been used for all tester strains. Quetiapine did produce a reproducible increase in mutations in one Salmonella typhimurium tester strain in the presence of metabolic activation. No evidence of clastogenic potential was obtained in the in vivo micronucleus assay in rats.Quetiapine can be life-threatening if abused or misused. Toxicity is associated with levels greater than 1500 ng/mL in serum or plasma. Supportive care is the mainstay of treatment. In acute toxicity, measures are necessary to maintain the airway and ensure adequate oxygenation and ventilation. Gastric lavage and activated charcoal administration alongside a laxative to prevent further drug absorption are used if time appropriate. Plasma concentrations of quetiapine reach maximal levels within 1 to 2 hours of oral administration. ECG is a recommendation to monitor for possible Torsades de pointes or another arrhythmia due to QT-interval prolongation. Treat extrapyramidal effects with anticholinergic and hypotension with intravenous fluids and sympathomimetic agents such as A1 agonists. Management/treatment of neuroleptic malignant syndrome is possible by immediate withdrawal of quetiapine, followed by the management of symptoms.The mechanism of action of quetiapine, as with other drugs used to treat schizophrenia, is unknown. However, it is thought that the drug's therapeutic activity in schizophrenia is mediated through a combination of dopamine type 2 (D2) and serotonin type 2 (5HT<sub>2</sub>) receptor antagonism. Although quetiapine is known to bind other receptors with similar affinity, only the dopamine D2 and serotonin 5HT<sub>2</sub> receptor binding is responsible for quetiapine's therapeutic activity in schizophrenia.
Signs and Symptoms	Symptoms of overdose include drowsiness and sedation, tachycardia, and hypotension.
Soil Adsorption/Mobility	Using a structure estimation method based on molecular connectivity indices(1), the Koc of quetiapine can be estimated to be 3.2X10+4(SRC). According to a classification scheme(2), this estimated Koc value suggests that quetiapine is expected to be immobile in soil. The estimated pKa values of quetiapine are 2.78 and 7.46(3), indicating that this compound will exist partially in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).
Gefahrstoffdaten	111974-69-7(Hazardous Substances Data)

Anwendungen & Verwendung

Verwenden

Labelled Quetiapine (Q510000). Used as an antipsychotic.