What is the mechanism of action (MOA) of Crestor (rosuvastatin)?

From the Guidelines

Crestor (rosuvastatin) works by inhibiting HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis in the liver, thereby reducing the liver's production of low-density lipoprotein (LDL) cholesterol and increasing the number of LDL receptors on liver cells to enhance the uptake and clearance of LDL from the bloodstream. This mechanism of action is supported by studies such as 1, which describes the effects of HMG-CoA reductase inhibitors, including rosuvastatin, on lipid profiles. The inhibition of HMG-CoA reductase reduces the production of mevalonate, a precursor of cholesterol, which in turn decreases the liver's production of LDL cholesterol. Additionally, rosuvastatin increases the number of LDL receptors on liver cells, enhancing the uptake and clearance of LDL from the bloodstream. This dual mechanism effectively lowers LDL cholesterol levels in the blood.

• Rosuvastatin also moderately reduces triglycerides and slightly increases high-density lipoprotein (HDL) cholesterol, as seen in studies such as 1.
• Compared to other statins, rosuvastatin is more hydrophilic, which limits its penetration into non-hepatic tissues and may contribute to its favorable side effect profile.
• The drug is typically dosed once daily (5-40 mg), with effects beginning within one week and reaching maximum effect after about four weeks of therapy, as described in 1.
• Rosuvastatin is primarily used to treat hypercholesterolemia and to reduce cardiovascular risk in patients with elevated cholesterol levels, as supported by studies such as 1 and 1.

From the FDA Drug Label

Rosuvastatin is an inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol. Inhibition of HMG-CoA reductase by rosuvastatin accelerates the expression of LDL-receptors, followed by the uptake of LDL-C from blood to the liver, leading to a decrease in plasma LDL-C and total cholesterol.

The mechanism of action (MOA) of Crestor (rosuvastatin) is the inhibition of HMG-CoA reductase, which is the rate-limiting enzyme responsible for converting 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol. This inhibition leads to an increase in the expression of LDL-receptors, resulting in the uptake of LDL-C from the blood to the liver, and ultimately decreasing plasma LDL-C and total cholesterol 2.

Key points:

• HMG-CoA reductase inhibition
• Increased LDL-receptor expression
• Decreased plasma LDL-C and total cholesterol

From the Research

Mechanism of Action (MOA) of Crestor (Rosuvastatin)

• Crestor (rosuvastatin) is a synthetic statin that works by inhibiting the enzyme HMG-CoA reductase, which plays a key role in the production of cholesterol in the liver 3, 4.
• Rosuvastatin has a high affinity for the active site of HMG-CoA reductase and exhibits greater potency in inhibiting enzyme activity and cholesterol synthesis in vitro than other statins 4.
• The drug is selectively taken up by hepatic cells, where it inhibits the production of low-density lipoprotein cholesterol (LDL-C) 3, 4.
• Rosuvastatin also has anti-inflammatory effects, which may contribute to its ability to reduce the risk of cardiovascular events 5.

Pharmacological Characteristics

• Rosuvastatin is a hydrophilic statin, which means it is relatively water-soluble and is not extensively metabolized by the cytochrome P450 enzyme system 3, 6.
• The drug has a long terminal half-life and is not significantly affected by inhibitors of the cytochrome P450 enzyme system 3.
• Rosuvastatin is well tolerated and has a safety profile comparable to other statins 3, 7, 5.

Clinical Efficacy

• Rosuvastatin has been shown to reduce LDL-C levels by up to 63% and increase high-density lipoprotein cholesterol (HDL-C) levels by up to 14% 3.
• The drug has also been shown to reduce the risk of major cardiovascular events in patients with normal LDL-C levels and elevated high-sensitivity C-reactive protein (hsCRP) levels 5.
• Rosuvastatin has been compared to other statins, such as atorvastatin, simvastatin, and pravastatin, and has been shown to be more effective in reducing LDL-C levels 3, 7, 6.