Zyrova Mechanism of Action

Pharmacotherapeutic group: HMG-CoA reductase inhibitors.
Pharmacology: Pharmacodynamics: 5 mg: Mechanism of action: Rosuvastatin is a selective and competitive 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. Rosuvastatin increases the number of hepatic LDL receptors on the cell-surface, enhancing uptake and catabolism of LDL and it inhibits the hepatic synthesis of VLDL, thereby reducing the total number of VLDL and LDL particles.
10 mg and 20 mg: Zyrova contains rosuvastatin calcium which is a new synthetic lipid-lowering agent. Rosuvastatin is a selective competitive inhibitor of the enzyme, 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol synthesis.
Rosuvastatin is a potent lipid-lowering drug which has been shown to lower the elevated total cholesterol, low-density lipoprotein (LDL)-cholesterol, very low-density lipoprotein (VLDL)-cholesterol, serum triglycerides and ApoB levels. It has also been shown to raise the high-density lipoprotein (HDL)-cholesterol and ApoA-1 levels. Rosuvastatin also lowers the LDL-C/HDL-C, total-C/HDL-C and nonHDL-C/HDL-C and the ApoB/ApoA-1 ratios. A therapeutic effect is obtained within 1 week following treatment initiation and 90% of maximum is achieved in 2 weeks. The maximum response is usually achieved by 4 weeks and is maintained thereafter. The primary site of action of rosuvastatin is the liver, the target organ for cholesterol lowering. Its primary mechanism for lowering LDL-C is by inhibiting conversion of HMG-CoA to mevalonate, a precursor for cholesterol, in the hepatocyte. Through competitive blockade of HMG-CoA reductase binding to HMG, the rate-limiting enzyme in cholesterol biosynthesis, this agent reduces the production of LDL-C. This in turn, results in up-regulation of LDL-C receptors on the hepatocytes and more rapid clearance of this lipoprotein from plasma.
40 mg: Mechanism of action: Rosuvastatin is a selective and competitive 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. Rosuvastatin increases the number of hepatic LDL receptors on the cell-surface, enhancing uptake and catabolism of LDL and it inhibits the hepatic synthesis of VLDL, thereby reducing the total number of VLDL and LDL particles.
Pharmacokinetics: 5 mg: Absorption: In clinical pharmacology studies in man, peak plasma concentrations of rosuvastatin were reached 3 to 5 hours following oral dosing. Both Cmax and AUC increased in approximate proportion to rosuvastatin dose. The absolute bioavailability of rosuvastatin is approximately 20%. Administration of rosuvastatin with food did not affect the AUC of rosuvastatin. The AUC of rosuvastatin does not differ following evening or morning drug administration.
Distribution: Mean volume of distribution at steady-state of rosuvastatin is approximately 134 liters. Rosuvastatin is 88% bound to plasma proteins, mostly albumin. This binding is reversible and independent of plasma concentrations.
Elimination: Rosuvastatin is primarily eliminated by excretion in the feces. The elimination half-life of rosuvastatin is approximately 19 hours.
Metabolism: Rosuvastatin is not extensively metabolized; approximately 10% of a radiolabeled dose is recovered as metabolite. The major metabolite is N-desmethyl rosuvastatin, which is formed principally by cytochrome P450 2C9, and in vitro studies have demonstrated that N-desmethyl rosuvastatin has approximately one-sixth to one-half the HMG-CoA reductase inhibitory activity of the parent compound. Overall, greater than 90% of active plasma HMG-CoA reductase inhibitory activity is accounted for by the parent compound.
Excretion: Following oral administration, rosuvastatin and its metabolites are primarily excreted in the feces (90%). After an intravenous dose, approximately 28% of total body clearance was via the renal route, and 72% by the hepatic route.
10 mg & 20 mg: Rosuvastatin achieves peak plasma concentrations in 3-5 hrs after a single dose and exhibits a terminal t_½ of approximately 19 hrs. It has a systemic bioavailability of approximately 20%. Systemic exposure of rosuvastatin increases in proportion to dose. It is about 88% bound to plasma proteins, mainly to albumin. Rosuvastatin is taken up extensively by the liver which is the primary site of cholesterol synthesis and LDL-C clearance. It undergoes limited metabolism (approximately 10%), primarily via the cytochrome P-450 CYP2C9 isoenzyme. The major metabolite identified is N-desmethyl rosuvastatin which has approximately 1/6 to ½ the HMG-CoA reductase inhibitory activity of rosuvastatin. Rosuvastatin accounts for >90% of the circulating HMG-CoA reductase inhibitor activity. Approximately 90% of the rosuvastatin dose is excreted unchanged in the feces (consisting of absorbed and non-absorbed active substances) and the remaining part is excreted in the urine. Approximately 5% is excreted unchanged in the urine.
40 mg: Rosuvastatin is incompletely absorbed from the gastrointestinal tract, with bioavailability of about 20%. Peak plasma concentrations are achieved about 5 hours after an oral dose. It is taken up extensively by the liver, its primary site of action, and undergoes limited metabolism, mainly by the cytochrome P450 isoenzyme CYP2C9. It is about 90% bound to plasma proteins. The plasma elimination half-life of rosuvastatin is about 19 hours. About 90% of an oral dose of rosuvastatin is excreted in the faeces, including absorbed and nonabsorbed drug, and the remainder is excreted in the urine; about 5% of a dose is excreted unchanged in urine.