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.

Simvastatin Action Pathway Xuan References