Rosuvastatin targets 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (IC₅₀ = 11 nM for enzyme inhibition in vitro; IC₅₀ = 1.12 nM for cholesterol biosynthesis inhibition in rat primary hepatocytes) [1]
Rosuvastatin targets human ether-a-go-go related gene (hERG) potassium channel (IKr) (IC₅₀ = 195 nM for hERG current blockade in hERG-transfected HEK293 cells) [2]

体外活性：瑞舒伐他汀相对亲水，对肝细胞有高度选择性；它的摄取是由肝脏特异性有机阴离子转运蛋白 OATP-C 介导的。 Rosuvastatin 是 OATP-C 的高亲和力底物，表观缔合常数为 8.5 μM。 Rosuvastatin 抑制大鼠肝脏离体肝细胞中的胆固醇生物合成，IC50 为 1.12 nM。瑞舒伐他汀引起的 LDL 受体 mRNA 增加大约是普伐他汀的 10 倍。 Rosuvastatin (100 μM) 降低 U937 对 TNF-α 刺激的 HUVEC 的粘附程度。 Rosuvastatin 通过抑制内皮细胞中的 c-Jun N 末端激酶和核因子-kB 来抑制 ICAM-1、MCP-1、IL-8、IL-6 和 COX-2 mRNA 和蛋白水平的表达。激酶测定：Rosuvastatin Calcium 是 HMG-CoA 还原酶的竞争性抑制剂，IC50 为 11 nM。细胞检测：瑞舒伐他汀具有相对亲水性，对肝细胞具有高度选择性；它的摄取是由肝脏特异性有机阴离子转运蛋白 OATP-C 介导的。 Rosuvastatin 是 OATP-C 的高亲和力底物，表观缔合常数为 8.5 μM。 Rosuvastatin 抑制大鼠肝脏离体肝细胞中的胆固醇生物合成，IC50 为 1.12 nM。瑞舒伐他汀引起的 LDL 受体 mRNA 增加大约是普伐他汀的 10 倍。 Rosuvastatin (100 μM) 降低 U937 对 TNF-α 刺激的 HUVEC 的粘附程度。 Rosuvastatin 通过抑制内皮细胞中的 c-Jun N 末端激酶和核因子-kB 来抑制 ICAM-1、MCP-1、IL-8、IL-6 和 COX-2 mRNA 和蛋白水平的表达。

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1. 瑞舒伐他汀（Rosuvastatin）（3a, S-4522）在体外可强效抑制HMG-CoA还原酶活性，IC₅₀为11 nM，抑制效力约为洛伐他汀钠的4倍；在大鼠原代肝细胞中，其抑制胆固醇合成的IC₅₀为1.12 nM，比普伐他汀强约100倍[1]
2. 在hERG转染的HEK293细胞中，瑞舒伐他汀（Rosuvastatin）以195 nM的IC₅₀阻断hERG电流；其对hERG的阻断作用受外排转运体（BCRP、MDR1）和内流转运体（OATP2B1）共表达的调控[2]
3. 在人诱导多能干细胞来源的心肌细胞（hiPSC-CMs）中，瑞舒伐他汀（Rosuvastatin）加速hERG通道失活，降低hERG电流幅值，延长动作电位时程（APD）；同时降低细胞膜上成熟hERG蛋白的表达，通过转录因子Sp1下调hERG mRNA表达（经Sp1 siRNA敲低和激动剂表儿茶素验证），并减少热休克蛋白70（Hsp70）与hERG蛋白的相互作用（干扰hERG折叠）[3]
4. 瑞舒伐他汀（Rosuvastatin）可激活未折叠蛋白反应（UPR）的关键介导因子ATF6，上调参与通道折叠的分子伴侣钙连蛋白和钙网蛋白的表达；在hiPSC-CMs中，hERG通道的降解同时通过溶酶体和蛋白酶体途径介导[3]
5. 在离体豚鼠心脏中，195 nM的瑞舒伐他汀（Rosuvastatin）可使90%复极化时的单相动作电位时程（MAPD₉₀）延长11±1 ms（基础周期250 ms，p<0.05）[2]

在清醒且不受约束的豚鼠中，瑞舒伐他汀（10 mg/kg，腹腔注射）可将 QTc 从 201±1 毫秒延长至 210±2 毫秒[2]。在链佐星产生的糖尿病大鼠中，瑞舒伐他汀（20 mg/kg/天）显着降低极低密度脂蛋白（VLDL）[4]。

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1. 对清醒未束缚的豚鼠腹腔注射瑞舒伐他汀（Rosuvastatin）（10 mg/kg），可使校正QT间期（QTc）从201±1 ms延长至210±2 ms（p<0.05）[2]
2. 在高胆固醇血症患者的临床研究中（疗程6-52周），瑞舒伐他汀（Rosuvastatin）改善血脂谱的效果优于阿托伐他汀、辛伐他汀和普伐他汀；在一项为期1年的剂量滴定研究中，瑞舒伐他汀（Rosuvastatin）（平均剂量13.4 mg/天）使98%的患者达到美国国家胆固醇教育计划（NCEP）的低密度脂蛋白胆固醇（LDL-C）靶标，而阿托伐他汀（平均剂量20.8 mg/天）组的达标率为87%，在高危患者中差异更为显著（97% vs 61%）[4]
3. 在另一项为期1年的临床试验中，瑞舒伐他汀（Rosuvastatin）（平均剂量9.5/13.8 mg/天）组的患者LDL-C达标率为88%，普伐他汀（20 mg/天）组为60%，辛伐他汀（20 mg/天）组为73%，且在高危患者中这一差异更明显[4]
4. 临床试验显示，瑞舒伐他汀（Rosuvastatin）可改善杂合子/纯合子家族性高胆固醇血症、高甘油三酯血症及混合性血脂异常患者的血脂谱[4]

1. HMG-CoA还原酶活性检测实验：制备HMG-CoA还原酶酶制剂，将其与系列浓度的瑞舒伐他汀（Rosuvastatin）（3a, S-4522）及底物HMG-CoA在适宜的反应条件（温度、pH）下共同孵育，通过检测反应产物的生成量或底物的消耗量评估酶活性，绘制剂量-反应曲线并计算IC₅₀；以洛伐他汀钠为阳性对照，比较抑制效能[1]
2. hERG通道电流记录实验（膜片钳技术）：将hERG转染的HEK293细胞接种并培养至贴壁单层，采用全细胞膜片钳技术，设置特定的电压钳制方案（去极化和复极化脉冲），记录不同浓度瑞舒伐他汀（Rosuvastatin）作用下的hERG电流，分析电流幅值变化并绘制剂量-反应曲线，计算hERG阻断的IC₅₀；实验中保持细胞外液和内液的离子组成、渗透压及pH稳定[2]

1. 大鼠原代肝细胞胆固醇合成抑制实验：分离大鼠原代肝细胞，接种于培养板并培养至贴壁，加入系列浓度的瑞舒伐他汀（Rosuvastatin），同时加入放射性标记的前体物质（如[¹⁴C]乙酸盐）；孵育一定时间后提取细胞内胆固醇，通过液闪计数检测放射性强度，计算胆固醇合成的抑制率，绘制剂量-反应曲线并确定IC₅₀，以普伐他汀为对照[1]
2. hERG转染HEK293细胞功能实验：将hERG基因转染至HEK293细胞，建立稳定表达细胞株；培养后加入不同浓度的瑞舒伐他汀（Rosuvastatin），通过膜片钳记录hERG电流，检测共表达的转运体（BCRP、MDR1、OATP2B1）对hERG阻断作用的影响，分析转运体表达水平与瑞舒伐他汀抑制效果的关联；设置空白对照组和溶剂对照组，排除非特异性影响[2]
3. hiPSC-CMs电生理与蛋白表达实验：培养人诱导多能干细胞来源的心肌细胞（hiPSC-CMs），加入不同浓度的瑞舒伐他汀（Rosuvastatin）处理后，采用膜片钳技术记录动作电位，分析APD的变化；通过Western blot检测细胞膜上hERG蛋白（成熟型和未成熟型）的表达，采用RT-PCR检测hERG mRNA的表达；利用siRNA敲低Sp1或加入Sp1激动剂表儿茶素，验证Sp1在hERG表达调控中的作用；通过免疫共沉淀检测Hsp70与hERG的相互作用，采用Western blot检测ATF6、钙连蛋白、钙网蛋白的表达，分析未折叠蛋白反应的激活情况；利用溶酶体抑制剂和蛋白酶体抑制剂处理细胞，检测hERG蛋白的降解变化以确定降解途径[3]

20 mg/kg/day
Male beagle dogs and Monkey

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1. Isolated Guinea Pig Heart Electrophysiology Experiment: Adult male guinea pigs were sacrificed, and hearts were rapidly excised and perfused with oxygenated Tyrode’s solution using the Langendorff method (stable temperature, flow rate, and oxygen partial pressure). Monophasic action potentials (MAP) were recorded by placing electrodes on the myocardial surface. 195 nM Rosuvastatin was added to the perfusate, and MAPD₉₀ changes were recorded for at least 10 minutes per concentration to ensure data reliability. The prolongation amplitude of MAPD₉₀ was calculated and statistically analyzed [2]
2. Guinea Pig In Vivo QTc Detection Experiment: Adult male guinea pigs were adaptively reared, then Rosuvastatin (10 mg/kg) was administered intraperitoneally (dissolved in a suitable vehicle such as normal saline or a solution with a small amount of cosolvent). Electrocardiograms were recorded by an electrocardiograph in conscious and unrestrained guinea pigs at different time points (0.5, 1, 2, 4 hours) before and after administration. QT intervals were measured and corrected to QTc based on heart rate, and changes in QTc before and after administration were compared. At least 7 guinea pigs were included in each group to ensure statistical power [2]

Absorption, Distribution and Excretion
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.
/MILK/ Limited data indicate that Crestor is present in human milk.
For more Absorption, Distribution and Excretion (Complete) data for Rosuvastatin (7 total), please visit the HSDB record page.

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Metabolism / Metabolites
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

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Biological Half-Life
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.

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1. Rosuvastatin is not extensively metabolized and has a low propensity for drug-drug interactions; [4]

Toxicity Summary
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 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.

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Hepatotoxicity
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, occurring in less than 1:10,000 patients. 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.
Likelihood score: A (likely cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Levels of rosuvastatin in milk are low, but no relevant published information exists with its use during breastfeeding. The consensus opinion is that women taking a statin should not breastfeed because of a concern with disruption of infant lipid metabolism. However, others have argued that children homozygous for familial hypercholesterolemia are treated with statins beginning at 1 year of age, that statins have low oral bioavailability, and risks to the breastfed infant are low, especially with rosuvastatin and pravastatin. Until more data become available, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
A possible case of rosuvastatin-induced gynecomastia has been reported. Serum prolactin was not measured.

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Protein Binding
Rosuvastatin is 88% bound to plasma proteins, mostly albumin. This binding is reversible and independent of plasma concentrations.

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Interactions
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.

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1. Rosuvastatin blocks hERG current, which is associated with an increased risk of long QT syndrome (LQTS); genetic polymorphisms of BCRP, MDR1, and OATP2B1 may further increase the risk of rosuvastatin-induced LQTS in some patients [2]
2. Rosuvastatin delays cardiac repolarization by reducing hERG expression and function, potentially inducing LQTS, torsade de pointes, and sudden cardiac death; no significant cytotoxicity (e.g., increased apoptosis) was observed in cell experiments, but abnormal hERG channels cause cardiac electrophysiological disorders [3]
3. Rosuvastatin was well tolerated in clinical trials of up to 1 year in duration; no severe hepatotoxicity, nephrotoxicity, or other major adverse reactions were reported [4]

[1]. Synthesis and biological activity of methanesulfonamide pyrimidine- and N-methanesulfonyl pyrrole-substituted 3,5-dihydroxy-6-heptenoates, a novel series of HMG-CoA reductase inhibitors. Bioorg Med Chem, 1997. 5(2): p. 437-44.

[2]. Rosuvastatin blocks hERG current and prolongs cardiac repolarization. J Pharm Sci. 2012 Feb;101(2):868-78.

[3]. Intracellular Mechanism of Rosuvastatin-Induced Decrease in Mature hERG Protein Expression on Membrane. Mol Pharm. 2019 Apr 1;16(4):1477-1488.

[4]. Rosuvastatin. Drugs, 2002. 62(14): p. 2075-85; discussion 2086-7.

Therapeutic Uses
Hydroxymethylglutaryl-CoA Reductase Inhibitors
/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Rosuvastatin is included in the database.
In individuals without clinically evident coronary heart disease but with an increased risk of cardiovascular disease based on age >/= 50 years old in men and >/= 60 years old in women, hsCRP >/= 2 mg/L, and the presence of at least one additional cardiovascular disease risk factor such as hypertension, low HDL-C, smoking, or a family history of premature coronary heart disease, Crestor is indicated to: reduce the risk of stroke, reduce the risk of myocardial infarction, reduce the risk of arterial revascularization procedures. /Included in US product label/
Crestor is indicated as adjunctive therapy to diet to slow the progression of atherosclerosis in adult patients as part of a treatment strategy to lower Total-C and LDL-C to target levels. /Included in US product label/
For more Therapeutic Uses (Complete) data for Rosuvastatin (11 total), please visit the HSDB record page.

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Drug Warnings
Crestor is contraindicated for use in pregnant women since safety in pregnant women has not been established and there is no apparent benefit to therapy with Crestor during pregnancy. Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, Crestor may cause fetal harm when administered to pregnant women. Crestor should be discontinued as soon as pregnancy is recognized.
Crestor should be prescribed with caution in patients with predisposing factors for myopathy (e.g., age >/= 65 years, inadequately treated hypothyroidism, renal impairment).
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).
Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, has been reported rarely in patients receiving statins. Immune-mediated necrotizing myopathy is characterized by proximal muscle weakness and elevated creatine kinase (CK, creatine phosphokinase, CPK) concentrations that persist despite discontinuance of statin therapy, necrotizing myopathy without substantial inflammation, and improvement following therapy with immunosuppressive agents.
For more Drug Warnings (Complete) data for Rosuvastatin (22 total), please visit the HSDB record page.

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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. 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.

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1. Rosuvastatin (3a, S-4522) is a novel methanesulfonamide pyrimidine-substituted 3,5-dihydroxy-6-heptenoate and a potent HMG-CoA reductase inhibitor; it was selected as a lead compound from a series of analogs due to its superior inhibitory activity [1]
2. Rosuvastatin is a methanesulfonamide derivative with a chemical structure similar to several IKr blockers (e.g., ibutilide, E-4031), which is the structural basis for its hERG-blocking effect [2]
3. Rosuvastatin reduces plasma membrane expression of hERG through two pathways: disrupting the trafficking of immature hERG channels to the membrane and increasing the degradation of mature hERG channels [3]
4. Rosuvastatin is indicated for the treatment of dyslipidemia; it shows better lipid-lowering efficacy than atorvastatin, simvastatin, and pravastatin in clinical trials, especially in high-risk hypercholesterolemia patients [4]

C22H28FN3O6S

481.54

481.168

287714-41-4

Rosuvastatin Calcium;147098-20-2;Rosuvastatin Sodium;147098-18-8;Rosuvastatin-d3 sodium;1279031-70-7;Rosuvastatin-d3;1133429-16-9;Rosuvastatin-d6 sodium;2070009-41-3;Rosuvastatin-d6 calcium

446157

Typically exists as solid at room temperature

1.368 g/cm3

745.6ºC at 760 mmHg

404.7ºC

2.38E-23mmHg at 25°C

1.597

2.147

152.13

3

10

10

33

767

2

S(C([H])([H])[H])(N(C([2H])([2H])[2H])C1=NC(C2C([H])=C([H])C(=C([H])C=2[H])F)=C(/C(/[H])=C(\[H])/[C@]([H])(C([H])([H])[C@]([H])(C([H])([H])C(=O)[O-])O[H])O[H])C(C([H])(C([H])([H])[H])C([H])([H])[H])=N1)(=O)=O.[Na+]

BPRHUIZQVSMCRT-VEUZHWNKSA-N

InChI=1S/C22H28FN3O6S/c1-13(2)20-18(10-9-16(27)11-17(28)12-19(29)30)21(14-5-7-15(23)8-6-14)25-22(24-20)26(3)33(4,31)32/h5-10,13,16-17,27-28H,11-12H2,1-4H3,(H,29,30)/b10-9+/t16-,17-/m1/s1

(3R,5S,E)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoate

ZD 4522; ZD-4522; ZD4522; S-4522; S 4522; S4522; Brand name: Crestor.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)