Simvastatin

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Warnung

• Sicherheit

  P201：Vor Gebrauch besondere Anweisungen einholen.

  P202：Vor Gebrauch alle Sicherheitshinweise lesen und verstehen.

  P280：Schutzhandschuhe/Schutzkleidung/Augenschutz tragen.

  P308+P313：BEI Exposition oder falls betroffen: Ärztlichen Rat einholen/ärztliche Hilfe hinzuziehen.

  P405：Unter Verschluss aufbewahren.

  P501：Inhalt/Behälter ... (Entsorgungsvorschriften vom Hersteller anzugeben) zuführen.

Simvastatin Chemische Eigenschaften,Einsatz,Produktion Methoden

• R-Sätze Betriebsanweisung:

  R36/37/38:Reizt die Augen, die Atmungsorgane und die Haut.

• S-Sätze Betriebsanweisung:

  S26:Bei Berührung mit den Augen sofort gründlich mit Wasser abspülen und Arzt konsultieren.
  S36:DE: Bei der Arbeit geeignete Schutzkleidung tragen.

• Beschreibung

  Simvastatin is an once-daily hypolipemic, an analog of lovastatin indicated for the treatment of atherosclerosis. In patients with Type IN or IIB hypercholesterolemia, simvastatin reportedly produces significant reductions in total serum cholesterol, LDL, mglycerides and apolipoprotein-B, while HDL and apolipoprotein-A levels are increased.

• Chemische Eigenschaften

  White Powder

• Originator

  Merck (USA)

• Verwenden

  A HMGCR inhibitor and anti-proliferative agent.

• Verwenden

  anti-hyperlipoproteinemic, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor

• Verwenden

  antiinflammatory

• Verwenden

  Simvastatin is semi-synthetic, slightly more hydrophobic, analogue of lovastatin. Like lovastatin, simvastatin is a specific inhibitor of HMG-CoA reductase and is used therapeutically to reduce LDL cholesterol. More recently, the statins have become important biochemical probes in cell biology. Their involvement in many events can be correlated to their primary mode of action, however, the mechanism of action of many other effects is less apparent.

• Verwenden

  Simvastatin is a synthetic derivative of a fermentation product of Aspergillus terreus. A competitive inhibitor of HMG-CoA reductase. A synthetic analog of Lovastatin. Antilipemic. Simvastatin, the dr ug, is sold under the trade name Zocor.

• Verwenden

  Simvastatin is a synthetic derivate of a fermentation product of Aspergillus terreus. A competitive inhibitor of HMG-CoA reductase. A synthetic analog of Lovastatin. Antilipemic. Simvastatin, the drug, is sold under the trade name Zocor.

• Definition

  ChEBI: A carbobicyclic compound that is lovastatin in which the 2-methylbutyrate ester moiety has been replaced by a 2,2-dimethylbutyrate ester group. It is used as a cholesterol-lowering and anti-cardiovascular disease drug.

• Manufacturing Process

  A suspension of Lovastatin (350 g, 0.865 mmol), phenylboronic acid (110.8 g, 0.909 mmol) and toluene (1.75 L) was heated under a nitrogen atmosphere at 100-105°C for 55 min. The water was separated from the reaction mixture. The solution was cooled and 1.39 L of toluene was removed by vacuum distillation at 40-50°C. The concentrated solution was treated with hexanes (3.15 L) at 40-50°C. The resulting suspension was cooled to 0-5C for 2 hours and the product was filtered and washed with hexanes (350 mL). The product was dried at 35-40°C under vacuum to provide 427.9 g (37%) of lovastatin phenylboronate at >99% purity by HPLC.
  A 2 L 3-necked flask was charged with pyrrolidine (56 mL, 0.67 mol) and dry THF (453 g) under a nitrogen atmosphere. n-Butyl lithium (419 mL, 1.6 M hexane solution, 0.67 mol) was added dropwise at -20°C over a period of 1 hour. The solution was maintained at this temperature for 30 min and then cooled to -55°C. A solution of lovastatin phenylboronate (101.7 g, 0.20 mol) in 274.7 g of THF was cooled to -50°C and then added to the cold lithium pyrrolidide solution at a rate such that the internal temperature was between -50°-55°C during the addition. The mixture was held at this temperature for 4 hours and then methyl iodide (116.4 g, 0.82 mol) was added at a temperature below -55°C. The reaction was stirred for 13 hours at -20°C and then quenched with 500 mL of 2 M HCl at a temperature below 0°C. After warming to 20°C, the layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with 5% NaHSO3 solution and deionized water. The solution was filtered through a Celite pad and concentrated to yield 102.8 g (98.4%) of crude Simvastatin phenylboronate at >95% purity by HPLC. A portion of the above material (50.0 g) was charged into a nitrogen purged flask with acetonitrile (100 mL). The suspension was heated at 110°C for 3 hours and then cooled to - 10°C for 1 hour. The product was filtered and washed with 25 mL of acetonitrile and dried under vacuum to provide 43.7 g of Simvastatin phenylboronate at >99% purity by HPLC.
  A suspension of simvastatin phenylboronate (30.0 g) and 1,3-propanediol (450 mL) was heated at 105-107°C at 0.2 mm Hg. After 1 hour, 182 mL of distillate was collected and the reaction was cooled to 20-25°C. Deionized water (270 mL) was added and toluene (3 times 75 mL) was used to extract the mixture. The combined toluene layers were washed with water (60 mL). The organic solution was heated at reflux for 1 hour and water was azeotropically removed. The solution was concentrated to a final volume of 24 mL under vacuum at 48-50°C. To the concentrated solution was added hexanes (215 mL) over 10 min. The resulting slurry was cooled to 0-5°C and filtered. The crude Simvastatin was washed at 0-5°C with hexanes and dried under vacuum to yield 21.0 g (88%) of Simvastatin.

• Trademarks

  Zocor (Merck);Zocord.

• Therapeutic Function

  Antihyperlipidemic

• Allgemeine Beschreibung

  Simvastatin, 2,2-dimethyl butanoic acid,1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2-pyran-2-yl)ethyl]-1-naphthalenyl ester(Zocor), is an analog of lovastatin. These two drugs havemany similar properties. Both drugs, in the prodrug form,reach the liver unchanged after oral administration, wherethey undergo extensive metabolism to several open-ring hydroxyacids, including the active -hydroxy acids. They arealso highly bound to plasma proteins. These actions makethe bioavailability of simvastatin rather poor but better thanthat of lovastatin, which has been estimated to be 5%.

• Biologische Aktivität

  HMG-CoA reductase inhibitor; decreases levels of low density lipoprotein. Has multiple biological effects including bone formation stimulation, inhibition of smooth muscle cell proliferation and migration, and anticancer and anti-inflammatory activity.

• Biochem/physiol Actions

  Simvastatin is a specific inhibitor of HMG-CoA reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early step in cholesterol biosynthesis. It is used in the treatment of hypercholesterolemia, as it reduces levels of low-density lipoproteins and triglycerides, and raises high-density lipoprotein levels. Simvastatin is a lactone that is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, and can be activated prior to use with NaOH in EtOH treatment. It is a synthetic analog of lovastatin (Cat. No. M2147).

• Clinical Use

  HMG CoA reductase inhibitor:
  Primary hypercholesterolaemia

• target

  TNF-α | NF-kB | MMP(e.g.TIMP) | p65 | JNK | Beta Amyloid | TGF-β/Smad | NO | NOS | STAT | IFN-γ

• Arzneimittelwechselwirkung

  Potentially hazardous interactions with other drugs
  Anti-arrhythmics: increased risk of myopathy with amiodarone - do not exceed 20 mg of simvastatin1 ; increased risk of myopathy with dronedarone.
  Antibacterials: increased risk of myopathy with clarithromycin, daptomycin, erythromycin and fusidic acid - avoid; possibly increased myopathy with azithromycin; concentration possibly reduced by rifampicin.
  Anticoagulants: effects of coumarins enhanced.
  Antiepileptics: concentration reduced by carbamazepine and eslicarbazepine.
  Antifungals: increased risk of myopathy with fluconazole, itraconazole, posaconazole, ketoconazole, voriconazole and possibly miconazole - avoid; possibly increased risk of myopathy with imidazoles.
  Antivirals: increased risk of myopathy with atazanavir, indinavir, lopinavir, ritonavir or saquinavir and possibly fosamprenavir, lopinavir or tipranavir - avoid; concentration reduced by efavirenz; avoid with boceprevir, dasabuvir, ombitasvir, paritaprevir and telaprevir; possible increased risk of myopathy with ledipasvir - reduce simvastatin dose; concentration increased by simeprevir - consider reducing simvastatin dose.
  Calcium-channel blockers: increased risk of myopathy with verapamil, diltiazem and amlodipine - do not exceed 20 mg of simvastatin.1
  Ciclosporin: increased risk of myopathy - avoid.1
  Cobicistat: avoid with simvastatin.
  Colchicine: possible increased risk of myopathy.
  Grapefruit: increased risk of myopathy - avoid.
  Hormone antagonists: possibly increased risk of myopathy with danazol - avoid.1
  Lipid-lowering agents: increased risk of myopathy with fibrates - do not exceed 10 mg of simvastatin except with fenofibrate1 ; gemfibrozil - avoid; concentration increased by lomitapide - do not exceed 40 mg of simvastatin; increased risk of myopathy with nicotinic acid.
  Ranolazine: concentration increased by ranolazine, maximum dose of simvastatin is 20 mg.
  Ticagrelor: concentration of simvastatin increased; maximum dose of simvastatin is 40 mg

• Stoffwechsel

  Simvastatin is absorbed from the gastrointestinal tract and must be hydrolysed to its active β-hydroxyacid form. Other active metabolites have been detected and several inactive metabolites are also formed. Simvastatin is a substrate for the cytochrome P450 isoenzyme CYP3A4 and undergoes extensive first-pass metabolism in the liver, its primary site of action. Less than 5% of an oral dose has been reported to reach the circulation as active metabolites.
  Simvastatin is mainly excreted in the faeces via the bile as metabolites. About 10-15% is recovered in the urine, mainly in inactive forms.

• Lager

  Desiccate at -20°C

• Einzelnachweise

  References/Citations 1) Merck 14:8539 2) Hancock et al. (1989), All ras proteins are polyisoprenylated but only some are palmitoylated; Cell, 57 1167 3) Ose et al. (2000), Lipid-altering efficacy and safety of simvastatin 80 mg/day: long-term experience in a large group of patients with hypercholesterolemia. World Wide Expanded Dose Simvastatin Study Group Clin. Cardiol. 23 39 4) Matsuzaka et al. (2016) Characterization and functional analysis of extracellular vesicles and muscle-abundant miRNA in C2C12 myocytes and Mdx mice; PLoS One 11(12) e0167811 [Focus Biomolecules Citation]

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