Rosetta Mechanism of Action

Pharmacotherapeutic group: HMG-CoA reductase inhibitors. ATC code: C10AA07.
Rosuvastatin is a hydrophilic statin.
Pharmacology: Pharmacodynamics: Mechanism of Action: Rosuvastatin is a selective and competitive inhibitor of 3-hydroxy-3-methylglutaryl-Coenzyme A (HMG-CoA) reductase, an enzyme that catalyzes the conversion of HMG-CoA to mevalonate. This conversion is an early and rate-limiting step in cholesterol biosynthesis.
By inhibiting this enzyme, rosuvastatin reduces plasma concentrations of total cholesterol and low-density lipoprotein-cholesterol (LDL-C), apolipoprotein B (Apo B), non-high-density lipoprotein-cholesterol (non-HDL-C) and triglyceride (TG), and increases high-density lipoprotein-cholesterol (HDL-C) concentrations in patients with primary hyperlipidemia or mixed dyslipidemia. Rosuvastatin also reduces TG concentrations in patients with primary hypertriglyceridemia.
The mechanism of the LDL-lowering effect may involve both reduction of very low-density lipoprotein (VLDL) synthesis and induction of the LDL receptors on hepatocyte membranes, leading to reduced production and/or increased uptake and catabolism of LDL.
A marked response was seen within 1 to 2 weeks, and the maximum therapeutic response occurred within 4 to 6 weeks. The response was maintained during therapy. Reductions in LDL are dose dependent and log linear. Therefore, LDL levels decreased by 6% with each doubling of the administered dose. In patients with TG levels higher than 200 mg/dL, TGs decrease in direct proportion to LDL decreases. In patients with very high TG levels, the LDL decreases are less than observed in patients with low TG levels.
Pharmacokinetics: Absorption: Rosuvastatin, the active moiety, is rapidly absorbed. Maximum rosuvastatin plasma concentrations are achieved approximately 3 to 5 hours after oral administration. The absolute bioavailability is approximately 20%.
Distribution: Rosuvastatin is taken up extensively by the liver which is the primary site of cholesterol synthesis and LDL-C clearance. The volume of distribution of rosuvastatin is approximately 134 liters. Approximately 90% of rosuvastatin is bound to plasma proteins, mainly to albumin.
Metabolism: Rosuvastatin undergoes limited metabolism (approximately 10%). In vitro metabolism studies using human hepatocytes indicate that rosuvastatin is a poor substrate for cytochrome P450-based metabolism. CYP2C9 was the principal isoenzyme involved, with 2C19, 3A4 and 2D6 involved to a lesser extent. The main metabolites identified are the N-desmethyl and lactone metabolites. The N-desmethyl metabolite is approximately 50% less active than rosuvastatin whereas the lactone form is considered clinically inactive. Rosuvastatin accounts for greater than 90% of the circulating HMG-CoA reductase inhibitor activity.
Excretion: Approximately 90% of the rosuvastatin dose is excreted unchanged in the faeces (consist of absorbed and non-absorbed active substance) and the remaining part is excreted in urine. Approximately 5% is excreted unchanged in urine. The plasma elimination half-life is approximately 19 hours. The elimination half-life does not increase at higher doses.
Special populations and conditions: Race: Pharmacokinetic studies show an approximate 2-fold elevation in median exposure to rosuvastatin (AUC and C_max) in Asian patients compared with Caucasian patients. Dosage of rosuvastatin should be adjusted in Asian patients.
Genetic polymorphisms: Disposition of statins, including rosuvastatin, involves the uptake transporter OATP1B1 and efflux transporter BCRP located in the liver, the major site of rosuvastatin action. In patients with SLCO1B1 (OATP1B1) and/or ABCG2 (BCRP) genetic polymorphisms there is a risk of increased rosuvastatin exposure.
Since rosuvastatin is the substrate of OATP1B1 and BCRP, attention should be paid to the OATP1B1 or BCRP-mediated drug-drug interaction of rosuvastatin in coadministration with other drugs that may inhibit the function of OATP1B1 or BCRP.
Hepatic impairment: Plasma concentrations of rosuvastatin are modestly increased in patients with chronic alcoholic liver disease. Peak plasma concentrations and AUC of rosuvastatin are increased by 60% and 5%, respectively, in patients with Child-Pugh class A disease and by 100% and 21%, respectively, in patients with Child-Pugh class B disease compared with individuals with normal liver function.
Rosuvastatin should be used with caution in patients with a history of liver disease (e.g., chronic alcoholic liver disease) and/or in patients who consume substantial amounts of alcohol.
Renal impairment: Exposure to rosuvastatin (i.e., plasma concentrations) does not appear to be influenced by mild or moderate renal impairment (creatinine clearance [CrCl] of 30 mL/min/1.73 m² or greater). However, plasma concentrations of rosuvastatin were increased to a clinically important extent (about 3-fold) in patients with severe renal impairment (CrCl less than 30 mL/min/1.73 m²) not undergoing hemodialysis compared with healthy individuals (CrCl greater than 80 mL/min/1.73 m²). Steady-state plasma concentrations of rosuvastatin in patients undergoing chronic hemodialysis were approximately 50% greater than those in healthy individuals with normal renal function.