indication

Used as an adjunct to dietary therapy to treat primary hypercholesterolemia (heterozygous familial and nonfamilial), mixed dyslipidemia and hypertriglyceridemia. Also indicated for homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering therapies or when other such therapies are not available.

pharmacology

Rosuvastatin is a synthetic, enantiomerically pure antilipemic agent. It is used to lower total cholesterol, low density lipoprotein-cholesterol (LDL-C), apolipoprotein B (apoB), non-high density lipoprotein-cholesterol (non-HDL-C), and trigleride (TG) plasma concentrations while increasing HDL-C concentrations. High LDL-C, low HDL-C and high TG concentrations in the plasma are associated with increased risk of atherosclerosis and cardiovascular disease. The total cholesterol to HDL-C ratio is a strong predictor of coronary artery disease and high ratios are associated with higher risk of disease. Increased levels of HDL-C are associated with lower cardiovascular risk. By decreasing LDL-C and TG and increasing HDL-C, rosuvastatin reduces the risk of cardiovascular morbidity and mortality.

mechanism of action

Rosuvastatin is a competitive inhibitor of HMG-CoA reductase. HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonate, an early rate-limiting step in cholesterol biosynthesis. Rosuvastatin acts primarily in the liver. Decreased hepatic cholesterol concentrations stimulate the upregulation of hepatic low density lipoprotein (LDL) receptors which increases hepatic uptake of LDL. Rosuvastatin also inhibits hepatic synthesis of very low density lipoprotein (VLDL). The overall effect is a decrease in plasma LDL and VLDL. In vitro and in vivo animal studies also demonstrate that rosuvastatin exerts vasculoprotective effects independent of its lipid-lowering properties. Rosuvastatin exerts an anti-inflammatory effect on rat mesenteric microvascular endothelium by attenuating leukocyte rolling, adherence and transmigration (PMID: 11375257). The drug also modulates nitric oxide synthase (NOS) expression and reduces ischemic-reperfusion injuries in rat hearts (PMID: 15914111). Rosuvastatin increases the bioavailability of nitric oxide (PMID: 11375257, 12031849, 15914111) by upregulating NOS (PMID: 12354446) and by increasing the stability of NOS through post-transcriptional polyadenylation (PMID: 17916773). It is unclear as to how rosuvastatin brings about these effects though they may be due to decreased concentrations of mevalonic acid.

toxicity

Generally well-tolerated. Side effects may include myalgia, constipation, asthenia, abdominal pain, and nausea. Other possible side effects include myotoxicity (myopathy, myositis, rhabdomyolysis) and hepatotoxicity. To avoid toxicity in Asian patients, lower doses should be considered. Pharmacokinetic studies show an approximately two-fold increase in peak plasma concentration and AUC in Asian patients (Philippino, Chinese, Japanese, Korean, Vietnamese, or Asian-Indian descent) compared to Caucasians patients.

biotransformation

Not extensively metabolized. Only ~10% is excreted as metabolite. Cytochrome P450 (CYP) 2C9 is primarily responsible for the formation of rosuvastatin's major metabolite, N-desmethylrosuvastatin. N-desmethylrosuvastatin has approximately 50% of the pharmacological activity of its parent compound in vitro. Rosuvastatin accounts for greater than 87% of the pharmacologic action. Inhibitors of CYP2C9 increase the AUC by less than 2-fold. This interaction does not appear to be clinically significant.

absorption

Bioavailability is approximately 20%

half life

19 hours

route of elimination

Rosuvastatin is not extensively metabolized; approximately 10% of a radiolabeled dose is recovered as metabolite. Following oral administration, rosuvastatin and its metabolites are primarily excreted in the feces (90%).

drug interactions

Colchicine: Increased risk of rhabdomyolysis with this combination

Cyclosporine: Cyclosporine may increase the serum concentration of rosuvastatin. Limit rosuvastatin dosing to 5 mg/day and monitor for changes in the therapeutic and adverse effects of rosuvastatin if cyclosporine is initiated, discontinued or dose changed.

Fenofibrate: May cause additive myotoxicity. Monitor for symptoms of muscle toxicity during concomitant therapy.

Gemfibrozil: Gemfibrozil may increase the therapeutic and toxic effects of rosuvastatin. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of rosuvastatin if gemfibrozil is initiated, discontinued or dose changed.

Magnesium: Magnesium-containing antacids may decrease the absorption of rosuvastatin.

Tipranavir: Concomitant therapy of Rosuvastatin and Tipranavir/Ritonavir may increase Rosuvastatin and Tipranavir concentrations. Consider alternate therapy.