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Pharmaceuticals -> Antilipidemics

Pharmaceuticals -> Statins

Pharmaceuticals -> Used in Switzerland

Pharmaceuticals -> Listed in ZINC15

Kow = 0.13 (pH 7.0) /log Kow = -0.88/

2.4

Sparingly soluble in water

8.86e-02 g/L

White powder from water as the monohydrate; begins to melt at 155 °C with no definitive MP. Specific optical rotation: +14.8 deg at 24 °C/D (c = 1.012 in 50% methanol). Sparingly soluble in water, methanol; slightly soluble in ethanol /Rosuvastatin calcium salt/

Positive

2.53

2.7

Agilent XCT

Electrospray ionization

formic acid (5.3nM)

Danger

H351 (90%): Suspected of causing cancer [Warning Carcinogenicity]

P203, P273, P280, P318, P391, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 10 reports by companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including rosuvastatin calcium, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Rosuvastatin calcium/

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. /Rosuvastatin calcium/

Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary. /Rosuvastatin calcium/

Store at controlled room temperature, 20-25 °C (68-77 °F). Protect from moisture.

Keep container tightly closed in a dry and well-ventilated place. Storage class (TRGS 510): Non Combustible Solids. /Rosuvastatin calcium/

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Avoid dust formation. Avoid breathing vapors, mist or gas. Environmental precautions: No special environmental precautions required. Methods and materials for containment and cleaning up: Sweep up and shovel. Keep in suitable, closed containers for disposal. /Rosuvastatin calcium/

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

Product: Offer surplus and non-recyclable solutions to a licensed disposal company; Contaminated packaging: Dispose of as unused product. /Rosuvastatin calcium/

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Avoid dust formation. Avoid breathing vapors, mist or gas. Environmental precautions: No special environmental precautions required. /Rosuvastatin calcium/

Precautions for safe handling: Further processing of solid materials may result in the formation of combustible dusts. The potential for combustible dust formation should be taken into consideration before additional processing occurs. Provide appropriate exhaust ventilation at places where dust is formed. /Rosuvastatin calcium/

Appropriate engineering controls: General industrial hygiene practice. /Rosuvastatin calcium/

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands. /Rosuvastatin calcium/

SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

Eye/face protection: Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). /Rosuvastatin calcium/

Skin protection: Handle with gloves. /Rosuvastatin calcium/

Body Protection: Choose body protection in relation to its type, to the concentration and amount of dangerous substances, and to the specific work-place. /Rosuvastatin calcium/

Respiratory protection: Respiratory protection is not required. Where protection from nuisance levels of dusts are desired, use type N95 (US) or type P1 (EN 143) dust masks. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). /Rosuvastatin calcium/

Concomitant use of rosuvastatin and ritonavir-boosted tipranavir produces minimal to no change in exposure to rosuvastatin. Following concomitant use of rosuvastatin (10 mg as a single dose) and ritonavir-boosted tipranavir (tipranavir 500 mg with ritonavir 200 mg twice daily for 11 days), rosuvastatin peak plasma concentration and AUC were increased by twofold and 26%, respectively. Caution is advised if rosuvastatin is used concomitantly with ritonavir-boosted tipranavir.

Concomitant use of rosuvastatin and antilipemic dosages (1 g daily or higher) of niacin may increase the risk of myopathy. Data from several large randomized studies indicate that concomitant use of niacin (1.5-2 g daily) with another statin (i.e., simvastatin 40-80 mg once daily, with or without ezetimibe) resulted in an increased risk of severe adverse effects, including disturbances in glycemic control requiring hospitalization, development of diabetes mellitus, adverse GI effects, myopathy, gout, rash, skin ulceration, infection, and bleeding. Caution is advised if rosuvastatin is used concomitantly with antilipemic dosages of niacin.

Following concomitant use of rosuvastatin (single 20-mg dose) with lomitapide (10 mg once daily for 7 days), peak plasma concentration and AUC of rosuvastatin were increased by 6 and 2%, respectively. Following concomitant use of rosuvastatin (single 20-mg dose) with lomitapide (60 mg once daily for 7 days), peak plasma concentration and AUC of rosuvastatin were increased by 4 and 32%, respectively. Dosage adjustment of rosuvastatin is not required during concomitant use with lomitapide.

Concomitant use of rosuvastatin (80 mg as a single dose) and ketoconazole (200 mg twice daily for 7 days) decreased rosuvastatin peak plasma concentration by 5% and increased rosuvastatin AUC by 2%.

For more Interactions (Complete) data for Rosuvastatin (25 total), please visit the HSDB record page.

Health effects include abdominal pain, dizziness, hypersensitivity (including rash, pruritus, urticaria, and angioedema) and pancreatitis. The following laboratory abnormalities have also been reported: dipstick-positive proteinuria and microscopic hematuria; elevated creatine phosphokinase, transaminases, glucose, glutamyl transpeptidase, alkaline phosphatase, and bilirubin; and thyroid function abnormalities (A308).

Rosuvastatin therapy is associated with mild, asymptomatic and usually transient serum aminotransferase elevations in 1% to 3% of patients. ALT levels above 3 times the upper limit of normal (ULN) occur slightly more frequently among rosuvastatin treated [1.1%] than placebo [0.5%] recipients. Serum enzyme elevations are more common with higher doses of rosuvastatin, being 2.2% with 40 mg daily. Most of these elevations are self-limited and do not require dose modification. Rosuvastatin is also associated with frank, clinically apparent hepatic injury but this is rare, estimated to occur in only 1:16,000 patients, a rate that is lower than atorvastatin (1:10,000) but higher than simvastatin (1:52,000). The onset is typically after 2 to 4 months and the pattern of serum enzyme elevations is usually hepatocellular, although cholestatic cases have also been reported. Rash, fever and eosinophilia are uncommon. Several statins including rosuvastatin have been linked to hepatitis with autoimmune features marked by ANA positivity, elevations in serum immunoglobulin levels, and a clinical response to corticosteroids. Such features are not, however, invariable (Case 1). The injury is usually self-limited and resolves rapidly once rosuvastatin is stopped, but it can be severe and fatal instances have been reported.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 48(SRC), determined from a structure estimation method(2), indicates that rosuvastatin is expected to have very high mobility in soil(SRC). The estimated pKa of rosuvastatin is 4.0(3), indicating that this compound will exist almost entirely in the anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization from moist soil is not expected because the compound exists as an anion and anions do not volatilize(SRC). Rosuvastatin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 5.3X10-19 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation half-lives of 3.1 and 5.2 days were reported for rosuvastatin calcium in the Modified OECD 302B test(5) suggesting that biodegradation of rosuvastatin may be an important environmental fate process in soil(SRC). However, <1% of rosuvastatin calcium was mineralized(5).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 48(SRC), determined from a structure estimation method(2), indicates that rosuvastatin is not expected to adsorb to suspended solids and sediment(SRC). The estimated pKa of 4.0(3) indicates rosuvastatin will exist almost entirely in the anion form at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process(SRC). According to a classification scheme(4), an estimated BCF of 3(SRC), from its log Kow of -0.88(5) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation half-lives of 3.1 and 5.2 days were reported for rosuvastatin calcium in the Modified OECD 302B test(6) suggesting that biodegradation of rosuvastatin may be an important environmental fate process in water(SRC). However, <1% of rosuvastatin calcium was mineralized(6).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), rosuvastatin, which has an estimated vapor pressure of 5.3X10-19 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase rosuvastatin may be removed from the air by wet and dry deposition(SRC). Rosuvastatin contains chromophores that absorb at wavelengths >290 nm(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

Inhalation. Bioavailability is approximately 20%. Peak plasma concentrations were reached 3 to 5 hours following oral dosing. Both Cmax and AUC increased in approximate proportion to CRESTOR dose. Food has no effect on the AUC of rosuvastatin.

EXPERIMENTAL: It is not known whether rosuvastatin is excreted in human milk. Studies in lactating rats have demonstrated that rosuvastatin is secreted into breast milk at levels 3 times higher than that obtained in the plasma following oral gavage dosing.

IDENTIFICATION AND USE: Rosuvastatin is hydroxymethylglutaryl-CoA reductase inhibitor. It is is indicated to reduce the risk of stroke, myocardial infarction, and arterial revascularization procedures. HUMAN EXPOSURE AND TOXICITY: Rosuvastatin is the most potent 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor commercially available to lower low-density lipoprotein cholesterol. Rosuvastatin has been associated with several adverse effects, including rhabdomyolysis and arthralgias. Myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported in patients receiving statins, including rosuvastatin. These adverse effects can occur at any dosage, but the risk is increased with the highest dosage of rosuvastatin (40 mg daily). There is a report of Takotsubo cardiomyopathy, triggered by delayed-onset rhabdomyolysis following the administration of long-term rosuvastatin treatment, without any preceding stressors or changes in the patient's medical condition, in association with complaints of non-specific muscle-related symptoms. Literature reported the case of a marathon runner who presented with acute rhabdomyolysis during competition while being under rosuvastatin treatment. A 77-year-old patient developed acute pancreatitis after treatment with rosuvastatin, which resolved on withdrawal of the medication. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including rosuvastatin. The genotoxic potential of rosuvastatin was assessed by chromosomal aberrations (CAs), micronucleus (MN) and DNA damage by comet assay in human peripheral blood lymphocytes. According to these results, rosuvastatin is cytotoxic and clastogenic/aneugenic in human peripheral lymphocytes. ANIMAL STUDIES: Rosuvastatin was shown to be of low acute toxicity following administration of single doses to rats and dogs by oral and intravenous routes. There were no mortalities in rats given an oral dose of 1000 mg/kg or 2000 mg/kg, and other than depression of bodyweight at 2000 mg/kg, there were no treatment-related effects at either dose level. Dogs received oral doses of 1000 mg/kg or 2000 mg/kg with vomiting on the day of dosing observed as the major clinical finding in both sexes. In a 104-week carcinogenicity study in rats at dose levels of 2, 20, 60 or 80 mg/kg/day, the incidence of uterine polyps was statistically significantly increased only in females at the dose of 80 mg/kg/day. In a 107-week carcinogenicity study in mice given 10, 60, 200 or 400 mg/kg/day, the 400 mg/kg/day dose was poorly tolerated, resulting in early termination of this dose group. An increased incidence of hepatocellular carcinomas was observed at 200 mg/kg/day and an increase in hepatocellular adenomas was seen at 60 and 200 mg/kg/day. Rosuvastatin administration did not indicate a teratogenic effect in rats at </= 25 mg/kg/day or in rabbits </= 3 mg/kg/day. In vitro, rosuvastatin was not mutagenic or clastogenic with or without metabolic activation in the Ames test with Salmonella typhimurium and Escherichia coli, L-5178 y +/- mouse lymphomas, and the chromosomal aberration assay in Chinese hamster lung cells. Rosuvastatin was negative in the in vivo mouse micronucleus test.

Signs and Symptoms of Overdose

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 (A2814). The drug also modulates nitric oxide synthase (NOS) expression and reduces ischemic-reperfusion injuries in rat hearts (A2818). Rosuvastatin increases the bioavailability of nitric oxide (A2814, 12031849, 15914111) by upregulating NOS (A2816) and by increasing the stability of NOS through post-transcriptional polyadenylation (A7824). It is unclear as to how rosuvastatin brings about these effects though they may be due to decreased concentrations of mevalonic acid.

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.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including rosuvastatin calcium, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Rosuvastatin calcium/

C10AA07

C - Cardiovascular system

QC - Cardiovascular system

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. Elevated cholesterol levels, and in particular, elevated low-density lipoprotein (LDL) levels, are an important risk factor for the development of CVD. Use of statins to target and reduce LDL levels has been shown in a number of landmark studies to significantly reduce the risk of development of CVD and all-cause mortality. Statins are considered a cost-effective treatment option for CVD due to their evidence of reducing all-cause mortality including fatal and non-fatal CVD as well as the need for surgical revascularization or angioplasty following a heart attack. Evidence has shown that even for low-risk individuals (with <10% risk of a major vascular event occurring within 5 years) statins cause a 20%-22% relative reduction in major cardiovascular events (heart attack, stroke, coronary revascularization, and coronary death) for every 1 mmol/L reduction in LDL without any significant side effects or risks. **Skeletal Muscle Effects** Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including rosuvastatin. These risks can occur at any dose level, but are increased at the highest dose (40 mg). Rosuvastatin should be prescribed with caution in patients with predisposing factors for myopathy (e.g., age ≥ 65 years, inadequately treated hypothyroidism, renal impairment). The risk of myopathy during treatment with rosuvastatin may be increased with concurrent administration of some other lipid-lowering therapies (such as [fenofibrate] or [niacin]), [gemfibrozil], [cyclosporine], [atazanavir]/[ritonavir], [lopinavir]/ritonavir, or [simeprevir]. Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors, including rosuvastatin, coadministered with [colchicine], and caution should therefore be exercised when prescribing these two medications together. Real-world data from observational studies has suggested that 10-15% of people taking statins may experience muscle aches at some point during treatment. **Liver Enzyme Abnormalities** Increases in serum transaminases have been reported with HMG-CoA reductase inhibitors, including rosuvastatin. In most cases, the elevations were transient and resolved or improved on continued therapy or after a brief interruption in therapy. There were two cases of jaundice, for which a relationship to rosuvastatin therapy could not be determined, which resolved after discontinuation of therapy. There were no cases of liver failure or irreversible liver disease in these trials. **Endocrine Effects** Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including rosuvastatin calcium tablets. Based on clinical trial data with rosuvastatin, in some instances these increases may exceed the threshold for the diagnosis of diabetes mellitus. An in vitro study found that [atorvastatin], [pravastatin], [rosuvastatin], and [pitavastatin] exhibited a dose-dependent cytotoxic effect on human pancreas islet β cells, with reductions in cell viability of 32, 41, 34 and 29%, respectively, versus control]. Moreover, insulin secretion rates were decreased by 34, 30, 27 and 19%, respectively, relative to control. HMG-CoA reductase inhibitors interfere with cholesterol synthesis and lower cholesterol levels and, as such, might theoretically blunt adrenal or gonadal steroid hormone production. Rosuvastatin demonstrated no effect upon nonstimulated cortisol levels and no effect on thyroid metabolism as assessed by TSH plasma concentration. In rosuvastatin treated patients, there was no impairment of adrenocortical reserve and no reduction in plasma cortisol concentrations. Clinical studies with other HMG-CoA reductase inhibitors have suggested that these agents do not reduce plasma testosterone concentration. The effects of HMG-CoA reductase inhibitors on male fertility have not been studied. The effects, if any, on the pituitarygonadal axis in premenopausal women are unknown. **Cardiovascular** Ubiquinone levels were not measured in rosuvastatin clinical trials, however significant decreases in circulating ubiquinone levels in patients treated with other statins have been observed. The clinical significance of a potential long-term statin-induced deficiency of ubiquinone has not been established. It has been reported that a decrease in myocardial ubiquinone levels could lead to impaired cardiac function in patients with borderline congestive heart failure. **Lipoprotein A** In some patients, the beneficial effect of lowered total cholesterol and LDL-C levels may be partly blunted by a concomitant increase in the Lipoprotein(a) [Lp(a)] concentrations. Present knowledge suggests the importance of high Lp(a) levels as an emerging risk factor for coronary heart disease. It is thus desirable to maintain and reinforce lifestyle changes in high-risk patients placed on rosuvastatin therapy. Further studies have demonstrated statins affect Lp(a) levels differently in patients with dyslipidemia depending on their apo(a) phenotype; statins increase Lp(a) levels exclusively in patients with the low molecular weight apo(a) phenotype.

Rosuvastatin is a statin medication and a competitive inhibitor of the enzyme HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase, which catalyzes the conversion of HMG-CoA to mevalonate, an early rate-limiting step in cholesterol biosynthesis. Rosuvastatin acts primarily in the liver, where 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, also known as the pleiotropic effects of statins. This includes improvement in endothelial function, enhanced stability of atherosclerotic plaques, reduced oxidative stress and inflammation, and inhibition of the thrombogenic response. Statins have also been found to bind allosterically to β2 integrin function-associated antigen-1 (LFA-1), which plays an important role in leukocyte trafficking and in T cell activation. Rosuvastatin exerts an anti-inflammatory effect on rat mesenteric microvascular endothelium by attenuating leukocyte rolling, adherence and transmigration. The drug also modulates nitric oxide synthase (NOS) expression and reduces ischemic-reperfusion injuries in rat hearts. Rosuvastatin increases the bioavailability of nitric oxide by upregulating NOS and by increasing the stability of NOS through post-transcriptional polyadenylation. It is unclear as to how rosuvastatin brings about these effects though they may be due to decreased concentrations of mevalonic acid.

Crestor 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.

The elimination half-life (t½) of rosuvastatin is approximately 19 hours and does not increase with increasing doses.

The elimination half-life of rosuvastatin is approximately 19 hours.

Rosuvastatin is not extensively metabolized, as demonstrated by the small amount of radiolabeled dose that is recovered as a metabolite (~10%). Cytochrome P450 (CYP) 2C9 is primarily responsible for the formation of rosuvastatin's major metabolite, N-desmethylrosuvastatin, which has approximately 20-50% of the pharmacological activity of its parent compound in vitro. However, this metabolic pathway isn't deemed to be clinically significant as there were no observable effects found on rosuvastatin pharmacokinetics when rosuvastatin was coadministered with fluconazole, a potent CYP2C9 inhibitor. In vitro and in vivo data indicate that rosuvastatin has no clinically significant cytochrome P450 interactions (as substrate, inhibitor or inducer). Consequently, there is little potential for drug-drug interactions upon coadministration with agents that are metabolized by cytochrome P450.

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 one-sixth to one-half the HMG-CoA reductase inhibitory activity of the parent compound. Overall, greater than 90% of active plasma HMG-CoA reductase inhibitory activity is accounted for by the parent compound.

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 clearance is not dependent on metabolism by cytochrome P450 3A4 to a clinically significant extent. Rosuvastatin accounts for greater than 90% 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%). After an intravenous dose, approximately 28% of total body clearance was via the renal route, and 72% by the hepatic route. Half Life: 19 hours

413KH5ZJ73

ROSUVASTATIN

Established Pharmacologic Class [EPC] - HMG-CoA Reductase Inhibitor

Mechanisms of Action [MoA] - Hydroxymethylglutaryl-CoA Reductase Inhibitors

Rosuvastatin is a HMG-CoA Reductase Inhibitor. The mechanism of action of rosuvastatin is as a Hydroxymethylglutaryl-CoA Reductase Inhibitor.

ROSUVASTATIN

Substances used to lower plasma CHOLESTEROL levels.

Compounds that inhibit HYDROXYMETHYLGLUTARYL COA REDUCTASES. They have been shown to directly lower CHOLESTEROL synthesis.

In a study of healthy white male volunteers, the absolute oral bioavailability of rosuvastatin was found to be approximately 20% while absorption was estimated to be 50%, which is consistent with a substantial first-pass effect after oral dosing. Another study in healthy volunteers found that the peak plasma concentration (Cmax) of rosuvastatin was 6.06ng/mL and was reached at a median of 5 hours following oral dosing. Both Cmax and AUC increased in approximate proportion to dose. Neither food nor evening versus morning administration was shown to have an effect on the AUC of rosuvastatin. Many statins are known to interact with hepatic uptake transporters and thus reach high concentrations at their site of action in the liver. Breast Cancer Resistance Protein (BCRP) is a membrane-bound protein that plays an important role in the absorption of rosuvastatin, particularly as CYP3A4 has minimal involvement in its metabolism. Evidence from pharmacogenetic studies of c.421C>A single nucleotide polymorphisms (SNPs) in the gene for BCRP has demonstrated that individuals with the 421AA genotype have reduced functional activity and 2.4-fold higher AUC and Cmax values for rosuvastatin compared to study individuals with the control 421CC genotype. This has important implications for the variation in response to the drug in terms of efficacy and toxicity, particularly as the BCRP c.421C>A polymorphism occurs more frequently in Asian populations than in Caucasians. Other statin drugs impacted by this polymorphism include [fluvastatin] and [atorvastatin]. Genetic differences in the OATP1B1 (organic-anion-transporting polypeptide 1B1) hepatic transporter have also been shown to impact rosuvastatin pharmacokinetics. Evidence from pharmacogenetic studies of the c.521T>C SNP showed that rosuvastatin AUC was increased 1.62-fold for individuals homozygous for 521CC compared to homozygous 521TT individuals. Other statin drugs impacted by this polymorphism include [simvastatin], [pitavastatin], [atorvastatin], and [pravastatin]. For patients known to have the above-mentioned c.421AA BCRP or c.521CC OATP1B1 genotypes, a maximum daily dose of 20mg of rosuvastatin is recommended to avoid adverse effects from the increased exposure to the drug, such as muscle pain and risk of rhabdomyolysis.

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%). After an intravenous dose, approximately 28% of total body clearance was via the renal route, and 72% by the hepatic route. A study in healthy adult male volunteers found that approximately 90% of the rosuvastatin dose was recovered in feces within 72 hours after dose, while the remaining 10% was recovered in urine. The drug was completely excreted from the body after 10 days of dosing. They also found that approximately 76.8% of the excreted dose was unchanged from the parent compound, with the remaining dose recovered as the metabolites n-desmethyl rosuvastatin and rosuvastatin-5S-lactone. Renal tubular secretion is responsible for >90% of total renal clearance, and is believed to be mediated primarily by the uptake transporter OAT3 (Organic anion transporter 1), while OAT1 had minimal involvement.

Rosuvastatin undergoes first-pass extraction in the liver, which is the primary site of cholesterol synthesis and LDL-C clearance. The mean volume of distribution at steady-state of rosuvastatin is approximately 134 litres.

In clinical pharmacology studies in man, peak plasma concentrations of rosuvastatin were reached 3 to 5 hours following oral dosing. Both Cmax and AUC increased in approximate proportion to Crestor dose. The absolute bioavailability of rosuvastatin is approximately 20%. Administration of Crestor with food did not affect the AUC of rosuvastatin. The AUC of rosuvastatin does not differ following evening or morning drug administration.

Mean volume of distribution at steady-state of rosuvastatin is approximately 134 liters. Rosuvastatin is 88% bound to plasma proteins, mostly albumin. This binding is reversible and independent of plasma concentrations.

Following oral administration, rosuvastatin and its metabolites are primarily excreted in the feces (90%). ... After an intravenous dose, approximately 28% of total body clearance was via the renal route, and 72% by the hepatic route.

Hydroxymethylglutaryl-CoA Reductase Inhibitors

MEDICATION

Use (kg; approx.) in Germany (2009): >100

Used as an adjunct to dietary therapy to treat primary hyperlipidemia (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. Furthermore, it is used to slow the progression of atherosclerosis and for primary prevention of cardiovascular disease.

The preparation of the intermediate ethyl 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidine-5-carboxylate occur according to standard chemical procedures. Reduction to the 5-hydroxymethyl derivative proceeds smoothly with diisobutylaluminum hydride (DIBALH) in toluene at -10 °C. The hydroxymethyl group is then converted to the bromo derivative, which upon reaction with triphenylphosphine affords the Wittig reagent. The latter is treated with tert-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate and provides the protected rosuvastatin ester. Removal of the dioxane protecting group by HCl, ester hydrolysis with NaOH and precipitation with CaCl2 gives /rosuvastatin/. The 6-formyl side chain intermediate is prepared by oxidation of the corresponding 6-hydroxymethyl compound, e.g., with DMSO-oxalyl chloride.

Preparation: K. Hirai et al., European Patent Office patent 521471; eidem, United States of America patent 5260440 (both 1993 to Shionogi).