Simvastatin

Molecular formula CzsHaeOs Molecular weight 418.6 CAS Registry No. 79902-63-9 

Sample preparation Microsomal incubations. 1 mL Microsomal incubation -I- 1 mL acetone, extract with 2 mL ethyl acetate. Remove the organic layer and dry it over anhydrous sodium sulfate, evaporate to dryness under a stream of nitrogen, reconstitute the residue in 200 pL n-propanol, inject a 20 p,L aliquot. Bile. Adjust pH of bile to 4. Extract 2 mL acidified bile with 10 mL MTBE ethyl acetate 75 25. Remove the organic layer and dry it over anhydrous sodium sulfate, evaporate to dryness under a stream of nitrogen, reconstitute the residue in 200 j,L n-propanol, inject a 20 jlL aliquot. Tissue. Homogenize liver with 4 volumes of water. Extract a 500 pL aliquot with 500 p,L MeCN. Evaporate the supernatant to dryness under a stream of nitrogen, reconstitute the residue in 200 xL n-propanol, inject a 20 jlL aliquot. 

Mobile phase Gradient. MeCN 5 mM formic acid from 30 70 to 90 10 over 30 min 

Stokker, G. Duggan, D.E. In vitro and in vivo biotransformation of simvastatin, an inhibitor of HMG CoA reductase. Drug Metab.Dispos., 1990, 18, 476-483 

Sample preparation 1 mL Plasma + 50 p.L MeCN water 60 40, shake at 150 cycles/min for 2 min, centrifuge at 1500 g for 3 min, remove the supernatant and extract the residue again with 400 pL MeCN, combine the supernatants, centrifuge, evaporate to dryness with a nitrogen stream under vacuum, reconstitute with 200 pL MeCN water 25 75, filter (0.45 pm), inject a 20 pL aliquot. 

Vickers, S. Duncan, C.A. Vyas, K.P. Kari, P.H. Arison, B. Prakash, S.R. Ramjit, H.G. Pitzenberger, S.M. Stokker, G. Duggan, D.E. In vitro and in vivo biotransformation of simvastatin, an inhibitor of HMG CoA reductase. Drug Metab.Dispos., 1990, 18, 476-483 

Retention time 7.2 (3.6 hydro or add form) Limit of detection 15 n mL Limit of quantitation 20 n mL 

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The cholesterol-lowering agents called statins, such as simvastatin (Zocor) and pravastatin (Pravachol), are among the most widely prescribed drugs in the world. Identify the functional groups in both, and tell how the two substances differ. 

Lovastatin, simvastatin Ketoconazole, erythromycin, etc. CYP3A4 Rhabdomyolysis... 

There are currently marketed four naturally derived statins (lovastatin, pravastatin, simvastatin, and rosuvas-tatin) and two synthetic statins (atorvastatin and fluvas-tatin). The structure of these statins is shown in Fig. 2. 

Lovastatin is taken once daily, preferably with the evening meal. Fluvastatin, pravastatin, and simvastatin are taken, witiiout regard to meals, once daily in die evening or at bedtime... 

QHi5ClSi 18162-48-6) see Caldpotriol Montelukast sodium Orlistat Simvastatin Tacrolimus (S)-4-(tert-butyldimethylsilyloxy)-2-hydroxybutyl 2-naph-thalenesulfonate... 

C23H4204Si 79902-31-1) see Simvastatin (2R,35,5lf)-3-[(l,l-dimethylethyl)dimethylsilyloxy]-2-hexyl-5-(phenylmethoxy)hexadecanoic acid... 

Figure 26-1. Biosynthesis of mevalonate. HMG-CoA reductase is inhibited by atorvastatin, pravastatin, and simvastatin. The open and solid circles indicate the fate of each of the carbons in the acetyl moiety ofacetyl-CoA.

In rodent stroke models, statin pretreatment has been shown to reduce infarct volumes and improve outcomes. Similarly, several clinical studies have shown that prior statin use reduced the severity of acute ischemic stroke and myocardial infarction. Recent studies indicate that beneftt can be achieved even when treatment is initiated after the onset of symptoms. In rodents, atorvastatin and simvastatin have been shown to reduce the growth of ischemic lesions, enhance functional outcome, and induce brain plasticity when administered after stroke onset. A retrospective analysis of the population-based Northern Manhattan Stroke Study (NOMASS) showed that patients using lipid-lowering agents at the time of ischemic stroke have a lower incidence of in-hospital stroke progression and reduced 90-day mortality rates. Retrospective analysis of data of the phase III citicoline trial showed... 

Corti R, Fayad ZA, Fuster V, Worthley SG, Helft G, Chesebro J, Mercuri M, Badimon JJ. Effects of lipid-lowering by simvastatin on human atherosclerotic lesions a longitudinal study by high-resolution, noninvasive magnetic resonance imaging. Circulation 2001 104(3) 249. 

McDonagh, J., Winocouri, P. and Walker, D.J. (1993). Musculoskeletal manifestations during simvastatin therapy. Lancet 32, 647-648. 

Amantadine, amiodarone, barbiturates, benzodiazepines, carbamazepine, chlorpromazine, fluoroquinolones, furosemide, NSAIDs, promethazine, psoralens, quinidine, simvastatin, sulfonamide antimicrobials, sulfonylureas, tetracyclines, and thiazides... 

Over the last decade, several studies in tens of thousands of patients have revealed that lowering cholesterol, specifically lowering LDL cholesterol with statins, is effective for both primary and secondary prevention of IHD-related events. Statins shown to decrease morbidity and mortality associated with IHD include lovastatin, simvastatin, pravastatin, and atorvas-tatin.22,23 A recent meta-analysis showed that the risk of major adverse cardiac events is reduced by 21% with the use of statins in patients at high risk for IHD-related events.23... 

Metoprolol 1 00 mg by mouth twice daily Hydrochlorothiazide 25 mg by mouth daily Vytorin 10/40 (ezetimibe 10 mg/simvastatin 40 mg) by mouth daily... 

GR is a 68-year-old African-American male who presents to the emergency department with dizziness and loss of speech that began 1 hour ago. His past medical history is significant for hypertension, diabetes mellitus, hypercholesterolemia, and benign prostatic hypertrophy (BPH). Social history is significant for smoking 1 pack per day for the last 38 years. Current medications include metoprolol 50 mg twice daily, insulin NPH 20 units twice daily, and simvastatin 20 mg daily. 

Lovastati n 1 0, 20, 40 mg tablets 1 0 to 80 mg/day as a single dose (with evening meal) or divided twice daily with food Approximate equivalent doses of HMG-CoA reductase inhibitors are atorvastatin 10 mg, fluvastatin 80 mg, lovastatin 40 mg, pravastatin 40 mg, simvastatin 20 mg, and rosuvastatin 5 mg. 

LC is a 51 -year-old female with a history of CHD (stent placement in the left anterior descending coronary artery 3 years prior) and type 2 diabetes who is referred to you for follow-up of her cholesterol. She is taking simvastatin 20 mg once daily in the evening for her cholesterol, and metformin 2000 mg once daily in the evening and piogliti-zone 15 mg once daily for diabetes. Her diabetes is well controlled. Her laboratory test results are within normal limits, except for her fasting lipid profile total cholesterol 215 mg/dL (5.57 mmol/L), triglycerides 135 mg/dL (1.53 mmol/L), HDL cholesterol 51 mg/dL (1.32 mmol/L), and LDL cholesterol 137 mg/dL (3.55 mmol/L). 

Hydrochlorothiazide 25 mg PO once daily Lisinopril 20 mg PO once daily Simvastatin 40 mg PO once daily at bedtime Aspirin 81 mg PO once daily... 

Simvastatin 20 mg by mouth once a day at bedtime Metoprolol 1 00 mg by mouth twice a day Aspirin 81 mg by mouth once a day... 

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