Simvastatin
|
Better Known as: Zocor
- Marketed By: Merck & Co. Inc.
- Major Indication: Hyperlipidemia & High Cholesterol (Hypercholesterolemia)
- Drug Class: HMGR Inhibitor or Statin
- Date of FDA Approval (Patent Expiration): 1997 (2006)
- 2005 Sales: $4.4 Billion [1]
- Why You Should Care: Zocor is one of the best selling drugs of all time and was the second best selling drug in 2005 before going off patent. Since statins are so ubiquitous, doctors have even suggested handing them out with fast food. See: the article
- The following is a list of Pharmacokinetic Parameters. See: Pharmaceutical Drugs for more information
Mechanism of Action
Simvastatin is an inhibitor of HMG-CoA Reductase (HMGR), a responsible for the committed step in cholesterol synthesis. Simvastatin, like most of the statins, via a number of polar interactions with the "cis loop" of HMGR, particularly residues Ser 684, Asp 690, Lys 691, Lys 692, and hydrogen bond interactions between Glu 559 and Asp 767 with the O5-hydroxyl of the statins. Van der Waals interactions between Leu 562, Val 683, Leu 853, Ala 856, and Leu 857 of HMGR and hydrophobic ring structures of Simvastatin contribute to binding as well.[2] These interactions help Simvastatin outcompete HMG-CoA, the substrate of HMGR, in binding to HMGR.[3]
Pharmacokinetics
| Statin PK Comparison at 10mg doses[4][5][6][7] | |||||
|---|---|---|---|---|---|
| Parameter | Atorvastatin (Lipitor) | Fluvastatin (Lescol) | Lovastatin (Mevacor) | Simvastatin (Zocor) | Rosuvastatin (Crestor) |
| Tmax (hr) | 2.5 | 1 | 3 | 1.5 | 4 |
| Cmax (ng/ml) | 27-66 | 448 | 10-20 | 7.3 | 4.34 |
| Bioavailability (%) | 12 | 19-29 | 5 | 5 | 20 |
| Protein Binding (%) | 80-90 | 99 | 95 | 95 | 88 |
| T1/2 (hr) | 15-30 | 2 | 3 | 2.7 | 19 |
| AUC (ng/ml/hr) | 104 | 33 | 125 | 48 | |
| IC50 (nM) | 154 | 198 | 800-4200 | 66 | 320 |
| Equivalent LDL Reduction Dosage (mg) | 10 | 80 | 20 | 5 | |
| Metabolism | Hepatic (CYP3A4) |
Hepatic (CYP2C9) |
Hepatic (CYP3A4) |
Hepatic (CYP3A4) |
Not Metabolized |
Effectiveness and Side Effects
Effectiveness
Side Effects
Although all of the statins are generally considered safe, rosuvastatin had a higher reported adverse event rate than other statin clinical trials. Typical adverse events include muscle weakness, headache dizziness and slightly increased creatinine kinase (CK) levels (an indication of kidney and smooth muscle damage), although these are common to all the statins (with the exception of elevated CK levels which only occurs in Atorvastatin, Rosuvastatin, and Simvastatin)[9] SEE http://www.druginjuryattorneyblog.com/2010/03/fda_warns_patients_that_choles.html
Interesting Facts
The Jist
References
- ↑ http://money.cnn.com/2006/06/23/news/companies/zoloft_zocor/index.htm
- ↑ Istvan ES, Deisenhofer J. Structural mechanism for statin inhibition of HMG-CoA reductase. Science. 2001 May 11;292(5519):1160-4. PMID:11349148 doi:10.1126/science.1059344
- ↑ Corsini A, Maggi FM, Catapano AL. Pharmacology of competitive inhibitors of HMG-CoA reductase. Pharmacol Res. 1995 Jan;31(1):9-27. PMID:7784310
- ↑ Bellosta S, Paoletti R, Corsini A. Safety of statins: focus on clinical pharmacokinetics and drug interactions. Circulation. 2004 Jun 15;109(23 Suppl 1):III50-7. PMID:15198967 doi:10.1161/01.CIR.0000131519.15067.1f
- ↑ Lins RL, Matthys KE, Verpooten GA, Peeters PC, Dratwa M, Stolear JC, Lameire NH. Pharmacokinetics of atorvastatin and its metabolites after single and multiple dosing in hypercholesterolaemic haemodialysis patients. Nephrol Dial Transplant. 2003 May;18(5):967-76. PMID:12686673
- ↑ Kiser JJ, Gerber JG, Predhomme JA, Wolfe P, Flynn DM, Hoody DW. Drug/Drug interaction between lopinavir/ritonavir and rosuvastatin in healthy volunteers. J Acquir Immune Defic Syndr. 2008 Apr 15;47(5):570-8. PMID:18176327 doi:10.1097/QAI.0b013e318160a542
- ↑ Li P, Callery PS, Gan LS, Balani SK. Esterase inhibition by grapefruit juice flavonoids leading to a new drug interaction. Drug Metab Dispos. 2007 Jul;35(7):1203-8. Epub 2007 Apr 23. PMID:17452418 doi:10.1124/dmd.106.013904
- ↑ Weng TC, Yang YH, Lin SJ, Tai SH. A systematic review and meta-analysis on the therapeutic equivalence of statins. J Clin Pharm Ther. 2010 Apr;35(2):139-51. PMID:20456733 doi:10.1111/j.1365-2710.2009.01085.x
- ↑ Weng TC, Yang YH, Lin SJ, Tai SH. A systematic review and meta-analysis on the therapeutic equivalence of statins. J Clin Pharm Ther. 2010 Apr;35(2):139-51. PMID:20456733 doi:10.1111/j.1365-2710.2009.01085.x