RiteMED Simvastatin Mechanism of Action

Pharmacology: Simvastatin is a gamma-lactone obtained by chemical modification of lovastatin. Hydrolysis of the lactone by esterases results in the dihydroxy acid known as simvastatin acid or SVA, which is the active form of the compound. This active metabolite is a competitive inhibitor of HMG-CoA reductase, a key rate-limiting enzyme in the cholesterol biosynthetic pathway, which catalyzes the conversion of HMG-CoA to mevalonate.
The main mechanism of reduction of low density lipoprotein (LDL) cholesterol is that, following inhibition of HMG-CoA reductase activity, the LDL receptor density on the liver cells is increased (up regulation) and this leads to increased removal of LDL cholesterol from plasma and increased catabolism of LDL cholesterol. In addition, there is decreased production of very low-density lipoprotein (VLDL) cholesterol and reduced formation of LDL from VLDL. Inhibition of HMG-CoA reductase does not lead to a build-up of intermediary metabolites since this enzyme is involved early in the synthetic pathway for cholesterol.
Simvastatin decreases total cholesterol, LDL cholesterol, triglycerides, and apolipoprotein B, while increasing HDL. In one head-to-head study of simvastatin versus pravastatin involving 291 patients, simvastatin produced slightly greater improvements in total cholesterol, LDL and HDL cholesterol, and triglycerides after 6 weeks. Both drugs were given in an oral dose of 10 mg once daily. Higher doses can produce more dramatic results. Bedtime administration of the drug is recommended since there is evidence for diurnal variation in the hepatic synthesis of cholesterol.
Pharmacokinetics: Simvastatin is a prodrug and must be activated in the liver. Absorption is about 85%, but bioavailability is 5% due to extensive presystemic metabolism. Absorption is not significantly reduced if taken before a low-fat meal, but to optimize the action of simvastatin, it should be administered at bedtime. Peak plasma concentrations are reached in 1.3-2.4 hours. Both simvastatin and its active metabolite, simvastatin acid, are strongly bound to plasma proteins (98%).
Simvastatin is extensively metabolized in the liver, which is also its main site of action. Sixty percent of an oral dose is excreted in the feces and 13% in the urine. Half-life of simvastatin is 1.9 hours.
Pharmacokinetic studies of single and multiple doses of simvastatin showed no accumulation of simvastatin during multiple dosing.
The effects of liver disease on the kinetics of simvastatin are not known.