Loading Pathway...
Error: Pathway image not found.
Hide
Pathway Description
Simvastatin Action Pathway
Homo sapiens
Drug Action Pathway
Simvastatin, the methylated form of lovastatin, is an inactive lactone that is metabolized in vivo to β,δ-dihydroxy acid, its most potent metabolite. Cytochrome P450 (CYP) enzymes, CYP3A4, CYP3A5, and CYP2C8, have been implicated in this activation step; CYP3A4/5 are responsible for ≥ 80% of simvastatin metabolism while CYP2C8 (not shown in pathway) contributes to ≤ 20% of its metabolism. The simvastatin hydroxy acid inhibits cholesterol synthesis via the mevalonate pathway by competitively inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. HMG-CoA reductase, a hepatic microsomal enzyme, is the enzyme responsible for the conversion of HMG-CoA to mevalonic acid, the rate-limiting step of cholesterol biosynthesis by this pathway. The active hydroxy acid is structurally similar to the reduced reaction intermediate and competes with HMG-CoA for binding to HMG-CoA reductase. Cholesterol biosynthesis accounts for approximately 80% of cholesterol in the body; thus, inhibiting this process can significantly lower cholesterol levels.
References
Steroid Biosynthesis References
Lehninger, A.L. Lehninger principles of biochemistry (4th ed.) (2005). New York: W.H Freeman.
Norman, A.W, and Litwack, G. Hormones (2nd ed.) (1997) San Diego : Academic Press.
Salway, J.G. Metabolism at a glance (3rd ed.) (2004). Alden, Mass.: Blackwell Pub.
Vance, D.E., and Vance, J.E. Biochemistry of lipids, lipoproteins, and membranes (4th ed.) (2002) Amsterdam; Boston: Elsevier.
Simons J: The $10 billion pill. Fortune. 2003 Jan 20;147(1):58-62, 66, 68.
Pubmed: 12602122
Simvastatin Pathway References
Ochiai H, Uchiyama N, Imagaki K, Hata S, Kamei T: Determination of simvastatin and its active metabolite in human plasma by column-switching high-performance liquid chromatography with fluorescence detection after derivatization with 1-bromoacetylpyrene. J Chromatogr B Biomed Sci Appl. 1997 Jun 20;694(1):211-7.
Pubmed: 9234865
Prueksaritanont T, Ma B, Yu N: The human hepatic metabolism of simvastatin hydroxy acid is mediated primarily by CYP3A, and not CYP2D6. Br J Clin Pharmacol. 2003 Jul;56(1):120-4.
Pubmed: 12848784
Reszka AA, Rodan GA: Bisphosphonate mechanism of action. Curr Rheumatol Rep. 2003 Feb;5(1):65-74.
Pubmed: 12590887
Schmidt, E.B., & Larsen, M.L. HMG-CoA-reductase-inhibitors. In S. Offermanns, & W. Rosenthal (Eds.). Encyclopedic reference of molecular pharmacology (2004);p. 460-463. Berlin, Germany: Springer.
Zocor. (2009). e-CPS (online version of Compendium of Pharmaceuticals and Specialties). Retrieved June 30, 2009.
Highlighted elements will appear in red.
Highlight Compounds
Highlight Proteins
Enter relative concentration values (without units). Elements will be highlighted in a color gradient where red = lowest concentration and green = highest concentration. For the best results, view the pathway in Black and White.
Visualize Compound Data
Visualize Protein Data
Settings