Stravas Mechanism of Action

Pharmacology: Pharmacodynamics: Rosuvastatin is a selective and competitive reductase inhibitor of HMG-CoA. HMG-CoA reductase is the rate-limiting enzyme in the conversion of 3-hydroxy-3-methylglutaryl-CoA to methylvalerate, a precursor of cholesterol. The results of animal and cell culture experiments showed that rosuvastatin was selectively taken up by the liver, which is a target organ for lowering cholesterol. In vivo and in vitro studies have shown that rosuvastatin increases the number of LDL receptors on the cell surface, thereby enhancing LDL uptake and catabolism, and inhibits liver VLDL synthesis, thereby reducing the total number of VLDL and LDL particles. In patients with homozygous and heterozygous familial hypercholesterolemia, non-familial hypercholesterolemia, and mixed dyslipidemia, rosuvastatin can reduce total cholesterol, LDL-C, ApoB, and non-HDL-C levels. Rosuvastatin also decreased TG and increased HDL-C levels. For patients with simple hypertriglyceridemia, rosuvastatin can reduce the levels of total cholesterol, LDL-C, VLDLC, ApoB, non-HDL-C, TG, and increase the level of HDL-C. The effect of rosuvastatin on cardiovascular incidence and mortality has not been determined.
Pharmacokinetics: Absorption: Peak plasma concentrations of Rosuvastatin were reached 5 hours following oral dosing. The absolute bioavailability of Rosuvastatin is approximately 20%.
Distribution: Rosuvastatin is ingested in large amounts by liver, which is a major organ for cholesterol synthesis and LDL-C clearance. Mean volume of distribution at steady-state of Rosuvastatin is approximately 134 liters. Rosuvastatin is approximately 90% bound to plasma proteins.
Metabolism: Rosuvastatin is not extensively metabolized; approximately 10% of a radiolabeled dose is recovered as metabolite. In vitro studies on the metabolism of human hepatocytes showed that rosuvastatin is a weak substrate for cytochrome P450 metabolism. The main isoenzyme involved in metabolism was CYP 2C9, and 2C19, 3A4 and 2D6 were less involved in metabolism. The known metabolites are N-demethylated and lactone metabolites. The N-demethylated metabolite was 50% less active than rosuvastatin, while the lactone metabolite was considered clinically inactive. Overall, greater than 90% of active plasma HMG-CoA reductase inhibitory activity is accounted for by the parent compound.
Elimination: Following oral administration, about 90% of Rosuvastatin and its metabolites are primarily excreted in the feces (including absorbed and unabsorbed active substance), the rest is excreted in the urine. About 5% in the urine is protoforma. The elimination half-life of Rosuvastatin is approximately 19 hours. The clearance period was not prolonged with the increase of dose. The geometric mean of plasma clearance was 50L/h (coefficient of variation 21.7%). As with other HMG-CoA reductase inhibitors, hepatic uptake of rosuvastatin involves the membrane transporter OATP-C. This transporter is important in liver clearance of rosuvastatin.