3-Hydroxy-3-Methylglutaryl Coenzyme A (HMG-CoA) Reductase Inhibitors

HMG-CoA reductase catalyzes the 4-electron reduction of HMG-CoA to CoA and mevalonate, with oxidation of two molecules of NADPH. Regulation of the expression of hepatic HMG-CoA reductase is critical in maintaining normal cholesterol levels in serum and tissues. HMG-CoA reductase inhibitors (statins) are competitive inhibitors of this enzyme and have hypocholesterolemic properties. These inhibitors have close resemblance to HMG-CoA. During cholesterol biosynthesis they competitively inhibit the conversion of HMG-CoA to mevalonate, thereby reducing cholesterol biosynthesis in hepatic cells. This results in the enhanced synthesis of LDL-C receptors and increased uptake of LDL-C particles, which enhances cholesterol clearance from the plasma. Ultimately, LDL-C and total cholesterol concentrations are reduced.

HMG-CoA reductase inhibitors differ in their pharmacokinetic properties and drug interaction profiles. For example, Lovastatin and Simvastatin are extensively metabolized by CYP3A4, an isozyme of the p450 system, and thus have the potential to interact with other drugs competing for or inhibiting this isoform. Both Lovastatin and Simvastatin are prodrugs in the lactone form and must be converted to active metabolites by the liver. On the other hand, pravastatin is not extensively metabolized by the p450 system. It is administered in its active hydroxyl acid form and is more hydrophilic and less protein-bound.