| 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. |
| Pharmacodynamics |
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.
|
| Absorption |
Bioavailability is approximately 20% |
| Volume of distribution |
|
| Protein binding |
90% bound to plasma proteins (mostly albumin) |
| Metabolism |
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. |
| 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%). |
| Half life |
19 hours |
| Clearance |
Not Available |
| 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. |
