Clinical pharmacology

General: In the bloodstream, cholesterol and triglycerides (TG) circulate as part of lipoprotein complexes. With ultracentrifugation, these complexes separate into very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL) fractions that contain apolipoprotein B-100 (ApoB-100) and high-density lipoprotein (HDL) fractions.
Cholesterol and TG synthesized in the liver are incorporated into VLDL and secreted into the circulation for delivery to peripheral tissues. TG are removed by the action of lipases, and in a series of steps, the modified VLDL is transformed first into IDL and then into cholesterol-rich LDL. IDL and LDL are removed from the circulation mainly by high affinity ApoB/E receptors, which are expressed to the greatest extent on liver cells. HDL is hypothesized to participate in the reverse transport of cholesterol from tissues back to the liver.
Epidemiologic, experimental, and clinical studies have established that high LDL cholesterol (LDL-C), low HDL cholesterol (HDL-C), and high plasma TG promote human atherosclerosis and are risk factors for developing cardiovascular disease. In contrast, higher levels of HDL-C are associated with decreased cardiovascular risk.
Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL, IDL, and remnants, can also promote atherosclerosis. Elevated plasma triglycerides are frequently found with low HDL-C levels and small LDL particles, as well as in association with non-lipid metabolic risk factors for coronary heart disease (CHD). As such, total plasma TG has not consistently been shown to be an independent risk factor for CHD. Furthermore, the
independent effect of raising HDL or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.
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. In vivo studies in animals, and in vitro studies in cultured animal and human cells have shown rosuvastatin to have a high uptake into, and selectivity for, action in the liver, the target organ for cholesterol lowering. In in vivo and in vitro studies,
rosuvastatin produces its lipid-modifying effects in two ways. First, it increases the number of hepatic LDL receptors on the cell-surface to enhance uptake and catabolism of LDL. Second, rosuvastatin inhibits hepatic synthesis of VLDL, which reduces the total number of VLDL and LDL particles.
Rosuvastatin reduces total cholesterol (total-C), LDL-C, ApoB, and nonHDL-C (total cholesterol minus HDL-C) in patients with homozygous and heterozygous familial hypercholesterolemia (FH), nonfamilial forms of hypercholesterolemia, and mixed dyslipidemia. Rosuvastatin also reduces TG and produces increases in HDL-C. Rosuvastatin reduces total-C, LDL-C, VLDL-cholesterol (VLDL-C), ApoB, nonHDL-C and TG, and increases HDL-C in patients with isolated hypertriglyceridemia. The effect of rosuvastatin on cardiovascular morbidity and mortality has not been determined.