Pharmacology: 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 of cholesterol. Rosuvastatin produces its lipid-modifying effects in 2 ways. First, it increases the number of hepatic low-density lipoprotein (LDL) receptors on the cell-surface to enhance uptake and catabolism of LDL. Second, rosuvastatin inhibits hepatic synthesis of very low-density lipoprotein (VLDL), which reduces the total number of VLDL and LDL particles.
Pharmacokinetics: Absorption: In clinical pharmacology studies in man, peak plasma concentrations of rosuvastatin were reached 3-5 hrs following oral dosing. Both Cmax and area under the curve (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 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% 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 1/6 to 1/2 the HMG-CoA reductase inhibitory activity of the parent compound. Overall, >90% of active plasma HMG-CoA reductase inhibitory activity is accounted for by the parent compound.
Excretion: Following oral administration, rosuvastatin and its metabolite are primarily excreted in the feces (90%). The elimination half-life (t½) of rosuvastatin is approximately 19 hrs. After an intravenous dose, approximately 28% of total body clearance was via the renal route and 72% by the hepatic route.