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Pharmacotherapeutic group: HMG-CoA reductase inhibitors. ATC code: C10A A07.
Pharmacology: Pharmacodynamics: Mechanism of action: Rosuvastatin is a selective, potent and competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol. Triglycerides (TG) and cholesterol in the liver arei ncorporated, with apolipoprotein B (ApoB), into very low density lipoprotein (VLDL) and released into the plasma for delivery to peripheral tissues. VLDL particles are TG-rich. Cholesterol-rich low density lipoprotein (LDL) is formed from VLDL and is cleared primarily through the high affinity LDL receptor in the liver.
Rosuvastatin produces its lipid-modifying effects in two ways; it 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.
High density lipoprotein (HDL), which contains ApoA-I is involved, amongst other things, in transport of cholesterol from tissues back to the liver (reverse cholesterol transport).
The involvement of LDL-C in atherogenesis has been well documented. Epidemiological studies have established that high LDL-C, TG, low HDL-C and ApoA-I have been linked to a higher risk of cardiovascular disease. Intervention studies have shown the benefits on mortality and CV event rates of lowering LDL-C and TG or raising HDL-C. More recent data has linked the beneficial effects of HMG-CoA reductase inhibitors to lowering of non-HDL (i.e. all circulating cholesterol not in HDL) and ApoB or reducing the ApoB/ApoA-I ratio.
Pharmacokinetics: Absorption: Peak plasma concentrations of Rosuvastatin were reached 3 to 5 hours following oral dosing. Both peak concentration (Cmax) and area under the plasma concentration-time curve (AUC) increased in approximate proportion to Rosuvastatin dose. The absolute bioavailability of Rosuvastatin is approximately 20%.
Administration of Rosuvastatin with food decreased the rate of drug absorption by 20% as assessed by Cmax, but there was no effect on the extent of absorption as assessed by AUC.
Plasma concentrations of Rosuvastatin do not differ following evening or morning drug administration.
Significant LDL-C reductions are seen when Rosuvastatin is given with or without food, and regardless of the time of day of drug administration.
Distribution: Mean volume of distribution at steady-state of Rosuvastatin is approximately 134 litres. Rosuvastatin is 88% bound to plasma proteins, mostly albumin. This binding is reversible and independent of plasma concentrations.
Metabolism: Rosuvastatin is not extensively metabolised; approximately 10% of a radiolabelled 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 Rosuvastatin. Overall, greater than 90% of active plasma HMG-CoA reductase inhibitory activity is accounted for by Rosuvastatin.
Excretion: Following oral administration, Rosuvastatin and its metabolite are primarily excreted in the faeces (90%). The elimination half-life (t½) of Rosuvastatin is approximately 19 hours. After an intravenous dose, approximately 28% of total body clearance was via the renal route and 72% by the hepatic route.
