simvastatin brands

Molecular formula: C25H38O5

Simvastatin is a prodrug in which the 6-membered lactone ring of simvastatin is hydrolyzed <i>in vivo</i> to generate the beta,delta-dihydroxy acid, an active metabolite structurally similar to HMG-CoA (hydroxymethylglutaryl CoA). Once hydrolyzed, simvastatin competes with HMG-CoA for HMG-CoA reductase, a hepatic microsomal enzyme, which catalyzes the conversion of HMG-CoA to mevalonate, an early rate-limiting step in cholesterol biosynthesis. Simvastatin acts primarily in the liver, where decreased hepatic cholesterol concentrations stimulate the upregulation of hepatic low density lipoprotein (LDL) receptors which increases hepatic uptake of LDL. Simvastatin also inhibits hepatic synthesis of very low density lipoprotein (VLDL). The overall effect is a decrease in plasma LDL and VLDL. At therapeutic doses, the HMG-CoA enzyme is not completely blocked by simvastatin activity, thereby allowing biologically necessary amounts of mevalonate to remain available. As mevalonate is an early step in the biosynthetic pathway for cholesterol, therapy with simvastatin would also not be expected to cause any accumulation of potentially toxic sterols. In addition, HMG-CoA is metabolized readily back to acetyl-CoA, which participates in many biosynthetic processes in the body. In vitro and in vivo animal studies also demonstrate that simvastatin exerts vasculoprotective effects independent of its lipid-lowering properties, also known as the pleiotropic effects of statins. This includes improvement in endothelial function, enhanced stability of atherosclerotic plaques, reduced oxidative stress and inflammation, and inhibition of the thrombogenic response. Statins have also been found to bind allosterically to β2 integrin function-associated antigen-1 (LFA-1), which plays an important role in leukocyte trafficking and in T cell activation. Simvastatin is a prodrug and is hydrolyzed to its active beta-hydroxyacid form, simvastatin acid, after administration. Simvastatin is a specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early and rate limiting step in the biosynthetic pathway for cholesterol. In addition, simvastatin reduces VLDL and TG and increases HDL-C. The HDL-associated enzyme paraoxonase protects LDLs from oxidative stress. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) appear to favorably influence the atherosclerotic process by different mechanisms. The present study examined the influence of simvastatin on paraoxonase expression and serum paraoxonase levels. Simvastatin upregulated in a dose-dependent manner the activity of the promoter of the paraoxonase gene in expression cassettes transfected into HepG2 cells. Upregulation could be blocked by mevalonate and other intermediates of the cholesterol biosynthetic pathway. Simvastatin increased nuclear factors, notably sterol regulatory element-binding protein-2, capable of binding to the paraoxonase promoter; this was also blocked by mevalonate. Sterol regulatory element-binding protein-2 upregulated promoter activity in vitro. Patients treated with statin showed a significant increase in serum concentrations and activities of paraoxonase. The data indicate that simvastatin can modulate expression in vitro of the antioxidant enzyme paraoxonase and is associated with increased serum paraoxonase concentration and activity. It is consistent with effects of simvastatin treatment, which have the potential to influence beneficially antiatherogenic mechanisms at the HDL level. The study provides evidence for 1 molecular mechanism by which paraoxonase gene expression could be regulated. ... We report in this work that, unexpectedly, simvastatin enhances LPS-induced IL-12p40 production by murine macrophages, and that it does so by activating the IL-12p40 promoter. Mutational analysis and dominant-negative expression studies indicate that both C/EBP and AP-1 transcri

Source: PubChem (NCBI) · compound 54454