Rovista Mechanism of Action

Pharmacology: Mechanism of Action: Rosuvastatin is a selective inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor for cholesterol. The primary site of action of rosuvastatin is the liver, the target organ for cholesterol lowering in in vivo and in vitro studies, rosuvastatin produces its lipid-modifying effects in 2 ways. First, it increases the number of hepatic LDL receptors on the cell surface to enhance uptake and catabolism of low-density lipoprotein (LDL). Second, rosuvastatin inhibits hepatic synthesis of very low-density lipoprotein (VLDL), which reduces the total number of VLDL and LDL particles.
Pharmacokinetics: Absorption: Maximum plasma concentration is achieved approximately in 5 hrs after oral administration. The absolute bioavailability is approximately 20%. Both peak concentration (C_max) and area under the plasma concentration-time curve (AUC) increased in approximately proportion to rosuvastatin dose.
Administration of rosuvastatin with food decreased the rate of drug absorption by 20% as assessed by C_max but there was no effect on the extent of absorption as assessed by AUC.
Distribution: Rosuvastatin is taken up extensively by the liver which is the primary site of cholesterol synthesis and LDL-C clearance. Mean volume of distribution at steady state of rosuvastatin is approximately 134 L. Rosuvastatin is 88% bound to plasma proteins, mostly albumin. This binding is reversible and independent of plasma concentrations.
Metabolism: Rosuvastatin is not extensively metabolized, (approximately 10%). The major metabolites is N-desmethyl (50% less active than parent), which is formed principally by cytochrome P-450 2C9, and lactone metabolite (clinically inactive). Rosuvastatin accounts for >90% of the circulating HMG-CoA reductase inhibitor activity.
Excretion: Following an oral administration, rosuvastatin and its metabolites are primarily excreted in the feces (90%) and approximately 5% is excreted unchanged in the urine. The elimination t_½ of rosuvastatin is approximately 19 hrs. The elimination t_½ does not increase at higher doses.
Special Populations: Renal Insufficiency: Subjects with varying degrees of renal impairment, mild to moderate renal disease had little influence on plasma concentrations of rosuvastatin. However, subjects with severe impairment (CrCl <30 mL/min) had a 3-fold increase in plasma concentration compared to healthy volunteers. Steady-state plasma concentration of rosuvastatin in patients on chronic hemodialysis were approximately 50% greater compared to healthy volunteer subjects with normal renal function.
Hepatic Insufficiency: In patients with chronic alcohol liver disease, plasma concentrations of rosuvastatin were modesty increased. In patients with Child-Pugh A disease, C_max and AUC were increased by 60% and 5% respectively, as compared with patients with normal liver function. In patients with Child-Pugh B disease, C_max and AUC were increased 100% and 21%, respectively, compared with patients with normal liver function.
Drug-Drug Relationship: Cyclosporine: Co-administration of cyclosporine with rosuvastatin resulted 11- and 7-fold increase in C_max and AUC of rosuvastatin respectively, compared with healthy subjects.
Gemfibrozil: Co-administration of a single rosuvastatin dose to healthy volunteers on gemfibrozil (600 mg twice daily) resulted in a 2.2- and 1.9-fold increase in mean C_max and mean AUC of rosuvastatin, respectively.
Antacid: Co-administration of an antacid (aluminum and magnesium hydroxide combination) with rosuvastatin (40 mg) resulted in a decrease in plasma concentrations of rosuvastatin by approximately 50%.
Oral Contraceptives: Co-administration of oral contraceptives (ethinyl estradiol and norgestrel) with rosuvastatin resulted in an increase in plasma concentrations of ethinyl estradiol and norgestrel by 28% and 34%, respectively.
Erythromycin: Concomitant use of rosuvastatin and erythromycin resulted in a 20% decrease in AUC and a 30% decreased in C_max of rosuvastatin.