HuagongsheHuagongshe Chemie-Druckbericht · Nur für Forschungszwecke
Amlodipine
AMLODIPINE BASE · besylate · Amlodipin · AmL · 3-ethyl 5-Methyl 2-((2-aMinoethoxy)Methyl)-4-(2-chlorophenyl)-6-Methyl-1,4-dihydropyridine-3,5-dicarboxylate · LOTREL · phytoxanthin · AMlodipine-d4 Maleate
Identifikatoren & physikalische Daten
| CAS No. | 88150-42-9 |
|---|---|
| Summenformel | C20H25ClN2O5 |
| Durchschnittliche Molmasse | 408,9 g/mol |
| Monoisotopische Masse | 408,14519958 g/mol |
| SMILES | CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl |
| InChIKey | HTIQEAQVCYTUBX-UHFFFAOYSA-N |
| PubChem CID | 2162 |
| ChEMBL | CHEMBL1491 |
| ChEBI | CHEBI:2668 |
| EC No. | 425-820-1 |
| DTXSID | DTXSID7022596 |
Chemische & physikalische Eigenschaften
| XLogP | 3 |
|---|---|
| Polarare Oberfläche (TPSA) | 99,9 |
| H-Brücken-Donoren | 2 |
| H-Brücken-Akzeptoren | 7 |
| Frei drehbare Bindungen | 10 |
| Schwere Atome | 28 |
| Formalladung | 0 |
| Komplexität | 647 |
| Arzneimittel | PharmaceuticalsPharmaceuticals -> Used in SwitzerlandPharmaceuticals -> Antihypertensives |
| LogP (Verteilungskoeffizient) | log Kow = 3.003.09 |
| Löslichkeit | slightly soluble in waterSoluble in DMSO (up to 25 mg/ml), in DMF (up to 25 mg/ml) or in Ethanol (up to 25 mg/ml).75.3 mg/L |
| Human Drugs | Breast FeedingLactationMilk, HumanAntihypertensive AgentsCalcium Channel BlockersVasodilator AgentsPharmaceuticalsAntihypertensive medicines |
| Animal Drugs | Pharmaceuticals -> UK Veterinary Medicines Directorate List |
| Decomposition | Hazardous decomposition products formed under fire conditions - Carbon oxides, nitrogen oxides (NOx), sulfur oxides, hydrogen chloride gas. /Amlodipine besylate/When heated to decomposition it emits toxic vapors of /nitric oxides/ and /hydrogen chloride/. |
| Schmelzpunkt | 199-201178-179°C |
| Physical Description | Solid |
| Stability/Shelf Life | Stable under recommended storage conditions. /Amlodipine besylate/ |
| Dissociation Constants | 9.26 |
| Collision Cross Section | 188 Ų [M+H]+ [CCS Type: TWMethod: Major Mix IMS/Tof Calibration Kit (Waters)] |
| Other Experimental Properties | Mol wt 524.95. White crystals from ethyl acetate, mp 178-179 °C /Amlopidine maleate/MW: 567.06. White crystalline powder. Slightly soluble in watersparingly soluble in ethanol /Amlodipine benzenesulfonate/ |
| Siedepunkt | 527.2±50.0 °C(Predicted) |
| Dichte | 1.227±0.06 g/cm3(Predicted) |
| Lagerbedingungen | Keep in dark place,Inert atmosphere,Store in freezer, under -20°C |
| pKa (Säurekonstante) | pKa 8.6 (Uncertain) |
| Aggregatzustand | Almost white crystal powder |
| Farbe | White |
| BCS Class | 1 |
| Stabilität | Stable for 1 year from date of purchase as supplied. Solutions in DMSO, DMF, or ethanol may be stored at -20°C for up to 3 months. |
| InChI | InChI=1S/C20H25ClN2O5/c1-4-28-20(25)18-15(11-27-10-9-22)23-12(2)16(19(24)26-3)17(18)13-7-5-6-8-14(13)21/h5-8,17,23H,4,9-11,22H2,1-3H3 |
| InChIKey | HTIQEAQVCYTUBX-UHFFFAOYSA-N |
| SMILES | C1(COCCN)NC(C)=C(C(OC)=O)C(C2=CC=CC=C2Cl)C=1C(OCC)=O |
| CAS Datenbank | 88150-42-9(CAS DataBase Reference) |
| EPA chemische Informationen | 3,5-Pyridinedicarboxylic acid, 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-, 3-ethyl 5-methyl ester (88150-42-9) |
Sicherheit & Vorschriften
| GHS-Einstufung | DangerH301: Toxic if swallowed [Danger Acute toxicity, oral]P260, P264, P264+P265, P270, P273, P280, P301+P316, P305+P354+P338, P317, P319, P321, P330, P391, P405, and P501 (click each P-code to see the statement)H301 (100%): Toxic if swallowed [Danger Acute toxicity, oral]P260, P264, P264+P265, P270, P273, P280, P301+P316, P302+P352, P305+P354+P338, P317, P319, P321, P330, P332+P317, P362+P364, P391, P405, and P501 (click each P-code to see the statement) |
|---|---|
| Regulatorische Informationen | Status: Active Update: 15-12-2008 https://echa.europa.eu/registration-dossier/-/registered-dossier/3689Amlodipine: Does not have an individual approval but may be used under an appropriate group standard |
| FDA-Anforderungen | The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including amlodipine besylate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Amlodipine besylate/ |
| Hazard Classes and Categories | Acute Tox. 3 (100%)Acute toxicity - category 3Acute Tox. 3 * |
| Hazardous Reactivities and Incompatibilities | Incompatible materials: Strong oxidizing agents. /Amlodipine besylate/ |
| Brandbekämpfungsverfahren | Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. /Amlodipine besylate/Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary. /Amlodipine besylate/ |
| Lagerbedingungen | Keep container tightly closed in a dry and well-ventilated place. /Amlodipine besylate/Store bottles at controlled room temperature, 59 deg to 86 °F (15 deg to 30 °C) and dispense in tight, light-resistant containers. |
| Reinigungsverfahren | ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Avoid breathing dust. Environmental precautions: 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. /Amlodipine besylate/ |
| 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.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 scrubberContaminated packaging: Dispose of as unused product. /Amlodipine besylate/ |
| Preventive Measures | ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Avoid breathing dust. Environmental precautions: Do not let product enter drains. /Amlodipine besylate/Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Further processing of solid materials may result in the formation of combustible dusts. The potential for combustible dust formation should be taken into consideration before additional processing occurs. Provide appropriate exhaust ventilation at places where dust is formed. /Amlodipine besylate/Appropriate engineering controls: Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday. /Amlodipine besylate/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. /Amlodipine besylate/For more Preventive Measures (Complete) data for AMLODIPINE (6 total), please visit the HSDB record page. |
| 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). /Amlodipine besylate/Skin protection: Handle with gloves. /Amlodipine besylate/Body Protection: Complete suit protecting against chemicals. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace. /Amlodipine besylate/Respiratory protection: For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator. For higher level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143) respirator cartridges. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). /Amlodipine besylate/ |
| Wechselwirkungen | This open-label, crossover study was performed to establish if there is evidence for interaction between telmisartan, an angiotensin II antagonist, and amlodipine, a class II (dihydropyridine) calcium channel antagonist, on the basis of pharmacokinetics and safety. In a two-way crossover trial, 12 healthy Caucasian males were randomized to receive once daily for 9 days oral amlodipine 10 mg with or without oral telmisartan 120 mg. After a washout period of > or = 13 days, the subjects were switched to the other medication regimen. The geometric means of the primary pharmacokinetic parameters at steady state (day 9) for amlodipine when given alone were the following: maximum plasma concentration (Cmax) 17.7 ng/mL, area under the plasma concentration-time curve (AUC) 331 ng.hr/mL, and renal clearance 39.5 mL/min, with 8% of the total amlodipine dose being excreted. When concomitant telmisartan was given, the respective values were 18.7 ng/mL, 352 ng.hr/mL, and 43.0 mL/min, with 9.4% of the total amlodipine dose being excreted renally. The limits of the 90% confidence intervals (CIs) for the ratios of these steady-state parameters were 0.97 to 1.14 for Cmax and 0.98 to 1.16 for AUCboth were within the predefined reference range (0.8 to 1.25) for bioequivalence. The high intersubject variability in urinary amlodipine excretion resulted in bioequivalence not being demonstrated for renal clearance. Adverse effects were few, mild to moderate in intensity, and transient whether amlodipine was given alone or with telmisartan. Vital signs, except for blood pressure, and clinical laboratory values were unaffected by either medication. The findings of this study show that concomitant telmisartan and amlodipine may be administered as there is no clinically significant variation in primary pharmacokinetic parameters of amlodipine in the presence of telmisartan, and the safety of the combination is comparable to that of amlodipine alone.Amlodipine is a representative calcium channel blocker that is frequently prescribed for the treatment of hypertension. In this study, the possibility of drug-drug interactions between amlodipine and coadministered antibiotics (ampicillin) was investigated in ratsthus, changes in the metabolic activities of gut microflora and the consequent pharmacokinetic pattern of amlodipine following ampicillin treatment were characterized. In human and rat fecalase incubation samples, amlodipine was metabolized to yield a major pyridine metabolite. The remaining amlodipine decreased and the formation of pyridine metabolite increased with incubation time, indicating the involvement of gut microbiota in the metabolism of amlodipine. Pharmacokinetic analyses showed that systemic exposure of amlodipine was significantly elevated in antibiotic-treated rats compared with controls. These results showed that antibiotic intake might increase the bioavailability of amlodipine by suppressing gut microbial metabolic activities, which could be followed by changes in therapeutic potency. Therefore, coadministration of amlodipine with antibiotics requires caution and clinical monitoring.1. The antinociceptive effects of amlodipine, administered subcutaneously (sc), intracerebroventricularly (icv) and intrathecally (it) were examined with the acetic acid writhing and tail-flick tests in mice. Amlodipine was also tested in combination with morphine and ketorolac. Isobolographic analyses were used to define the nature of functional interactions between amlodipine and morphine or ketorolac. 2. The s.c. (0.1, 1.25, 2.5, 5 and 10 mg/kg), icv (2.5, 5, 10 and 20 ug/mice) and it (2.5, 5, 10 and 20 ug/mice) administration of amlodipine exhibited a dose-dependent antinociceptive effect in the writhing test but had no effect on the tail-flick latency. Isobolographic analyses revealed an additive interaction between amlodipine and morphine or ketorolac in the writhing test. 3. These results suggest that amlodipine induces antinociception and increases antinociceptive action of morphine and ketorolac, possibly through a decrease in cellular calcium availability....The purpose of this study was to investigate drug interactions between amlodipine and simvastatin. Eight patients with hypercholesterolemia and hypertension were enrolled. They were given 4 weeks of oral simvastatin (5 mg/day), followed by 4 weeks of oral amlodipine (5 mg/day) co-administered with simvastatin (5 mg/day). Combined treatment with simvastatin and amlodipine increased the peak concentration (C(max)) of HMG-CoA reductase inhibitors from 9.6 +/- 3.7 ng/mL to 13.7 +/- 4.7 ng/mL (p < 0.05) and the area under the concentration-time curve (AUC) from 34.3 +/- 16.5 ng h/mL to 43.9 +/- 16.6 ng h/mL (p < 0.05) without affecting the cholesterol-lowering effect of simvastatin. ...For more Interactions (Complete) data for AMLODIPINE (13 total), please visit the HSDB record page. |
| Hepatotoxicity | Chronic therapy with amlodipine is associated with a low rate of serum enzyme elevations at rates that are similar to matched control populations. The enzyme elevations are usually mild, transient and asymptomatic and may resolve even during continued therapy. Clinically apparent liver injury from amlodipine is rare and described only in isolated case reports. In the few idiosyncratic cases reported, the latency period to onset of liver injury was usually 4 to 12 weeks, but examples with prolonged latency have also been published (10 months and several years). The latency period is shorter with recurrence on reexposure, including several instances of recurrence after liver injury due to other calcium channel blockers. The pattern of serum enzyme elevations is usually mixed or cholestatic. Rash, fever and eosinophilia have not been described and autoantibodies are not typical. |
| Umweltverhalten | TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 3200(SRC), determined from a structure estimation method(2), indicates that amlodipine is expected to have slight mobility in soil(SRC). Volatilization of amlodipine from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 2.9X10-17 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Amlodipine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.2X10-9 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). A biodegradation of 3% in 28 days using an aqueous ready biodegradability test(4) suggests that biodegradation is not an important environmental fate process in soil(SRC).AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 3200(SRC), determined from a structure estimation method(2), indicates that amlodipine 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 2.9X10-17 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 44(SRC), from its log Kow of 3.00(6) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is moderate(SRC). A biodegradation of 3% in 28 days using an aqueous ready biodegradability test(7) suggests that biodegradation is not an important environmental fate process in water(SRC).ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), amlodipine, which has an estimated vapor pressure of 1.2X10-9 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 amlodipine may be removed from the air by wet and dry deposition(SRC). Amlodipine contains chromophores that absorb at wavelengths >290 nm(4) and, therefore, may be susceptible to direct photolysis by sunlight(SRC). |
| Unerwünschte Wirkungen | The significant adverse effects of amlodipine include peripheral edema, heart failure, pulmonary edema, flushing, dizziness, headache, drowsiness, skin rash, nausea, abdominal pain, and constipation. Researchers observed edema, dizziness, flushing, and palpitations in controlled clinical trials in a dose-dependent manner. For example, at a dose of 10 mg, the incidence of edema, dizziness, flushing, and palpitations was 10.8%, 3.4%, 2.6%, and 4.5%, respectively. The incidence of headaches, fatigue, nausea, and abdominal pain was 7.3%, 4.5%, 2.9%, and 1.6%, respectively. |
| Toxizitätsübersicht | IDENTIFICATION AND USE: Amlodipine is calcium channel blocker used as antihypertensive and vasodilator agent. HUMAN EXPOSURE AND TOXICITY: One patient ingested 250 mg amlodipine and was asymptomatic. Another patient ingested 120 mg, underwent gastric lavage, and remained normotensive. A third patient took 105 mg and had hypotension (90/50 mmHG), which normalized following plasma expansion. A 19-month old ingested 30 mg (2 mg/kg) and had no evidence of hypotension but had a heart rate of 180 bpm. Children who ingested > 10 mg were 4.4 times more likely to develop clinically important responses than those ingesting < or = 5 mg. Hypotension may occur in children with amlodipine doses as low as 2.5 mg. ANIMAL STUDIES: Rats and mice treated with amlodipine maleate in the diet for up to two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 amlodipine mg/kg/day, showed no evidence of a carcinogenic effect of the drug. Amlodipine has been shown to prolong the duration of labor in rats. No evidence of teratogenicity or other embryo/fetal toxicity was observed in rats or rabbits given up to 10 mg/kg during periods of major organogenesis. However, the number of intrauterine deaths increased about five-fold, and rat litter size was decreased by 50%. Mutagenicity studies conducted with amlodipine maleate revealed no drug related effects at either the gene or chromosome level.Signs and Symptoms of Overdose |
| Soil Adsorption/Mobility | Using a structure estimation method based on molecular connectivity indices(1), the Koc of amlodipine can be estimated to be 3200(SRC). According to a classification scheme(2), this estimated Koc value suggests that amlodipine is expected to have slight mobility in soil. Amlodipine has the potential to adsorb to wastewater treatment plant biosolids(3). |
| Human Toxicity Excerpts | /SIGNS AND SYMPTOMS/ In postmarketing experience, jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), in some cases severe enough to require hospitalization, have been reported in association with use of amlodipine./SIGNS AND SYMPTOMS/ Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. In humans, experience with intentional overdosage of Norvasc is limited./CASE REPORTS/ A 35-year-old woman with a 9-year history of Grave's disease delivered a male infant weighing 2,210 g at 32 weeks of gestation by cesarean section. The neonate developed thyrotoxicosis and, at the age of 24 hr, was treated with oral carbimazole (500 ug every 8 hr) and propranolol (2 mg/kg/day in two divided doses). He subsequently developed hypertension on day 4, which required therapy with amlodipine (0.1 mg once daily). Severe hypotension developed within 24 hr and required discontinuation of amlodipine, with initiation of intravenous inotropic support with dopamine and dobutamine (at a rate of 20 ug/kg/min). The blood pressure rapidly normalized, and both dopamine and dobutamine infusions were stopped within 36 hr. A Naranjo assessment score of 6 was calculated, indicating that the severe hypotension was a probable adverse drug reaction caused by the combination of amlodipine and propranolol therapy./CASE REPORTS/ Amlodipine is a relatively new agent that has the longest half-life of all calcium channel blockers. This report describes a severe overdose that resulted in prolonged and severe hemodynamic compromise for up to 10 days, but responded to aggressive therapy with calcium, glucagon, and other vasoactive medicines.For more Human Toxicity Excerpts (Complete) data for AMLODIPINE (26 total), please visit the HSDB record page. |
| Artificial Pollution Sources | Amlodipine's production and administration as a medication(1) may result in its release to the environment through various waste streams(SRC). |
| Environmental Biodegradation | AEROBIC: Amlodipine reached 3% degradation in 28 days using a ready biodegradability test in water(1). |
| Drug Induced Liver Injury | Drug-Induced Liver Injury Severity and Toxicity (DILIst)amlodipineDILI PositiveOralDOI:10.1016/j.drudis.2019.09.022 |
| Environmental Bioconcentration | An estimated BCF of 44 was calculated in fish for amlodipine(SRC), using a log Kow of 3.00(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is moderate(SRC). |
| Volatilization from Water/Soil | The Henry's Law constant for amlodipine is estimated as 2.9X10-17 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that amlodipine is expected to be essentially nonvolatile from water and moist soil surfaces(2). Amlodipine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.2X10-9 mm Hg(SRC), determined from a fragment constant method(3). |
| UN-Transportnummer | UN2811 |
| Toxizität | TDLo orl-chd: 400 mg/kg:BPR AJEMEN 18,581,2000 |
| Gefahrenklasse | 6.1 |
| Gefahrstoffdaten | 88150-42-9(Hazardous Substances Data) |
Anwendungen & Verwendung
Beschreibung
Amlodipine is a dihydropyridine L-type calcium channel blocker that selectively inhibits calcium influx in cardiac and vascular smooth muscle. Acting as a vasodilator, amlodipine reduces blood pressure by relaxing the smooth muscle in the arterial wall, decreasing total peripheral resistance. It inhibits calcium-induced contractions in depolarized rat aorta with an IC50 value of 1.9 nM, displaying a slow rate of association and dissociation in isolated vascular and cardiac tissues. Amlodipine also demonstrates actions independent of L-type calcium channel blockade by regulating membrane fluidity and cholesterol deposition, stimulating nitric oxide production, acting as an antioxidant, and regulating matrix deposition in vitro and in vivo. Formulations containing amlodipine have been used in the treatment of hypertension.
History
Amlodipine was first patented in 1982 but approved as a prescription drug in 1990. Amlodipine is in the form of salt, the available salt forms are besilat, mesilate, and maleate. Amlodipine is an approved drug used to treat high blood pressure and coronary artery disease. Amlodipine is also sold under the brand name Norvasc. It was evaluated against diuretics in the treatment of hypertension and was found to be useful in controlling arterial pressure. In 2023, it was the fifth most commonly prescribed medication in the United States, with more than 68 million prescriptions.
Verwenden
A deuterated dihydropyridine calcium channel blocker.;Application of Labeled APIs: Labeled Amlodipine, intended for use as an internal standard for the quantification of Amlodipine by GC- or LC-mass spectrometry.