Selective inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase with the following inhibitory parameter:
- Ki = 0.16 nM (recombinant human HMG-CoA reductase), showing high affinity for the enzyme [2]
- Inhibitor of human ether-a-go-go-related gene (hERG) potassium channel (cardiac repolarization channel) with the following inhibitory parameter:
- IC50 = 15 μM (hERG current in HEK293 cells stably expressing hERG) [3]

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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抑制HMG-CoA还原酶与胆固醇合成：
- 在重组人HMG-CoA还原酶实验中，瑞舒伐他汀钙（Rosuvastatin Calcium） （0.01~10 nM）浓度依赖性抑制酶活性：0.1 nM抑制50%活性（与Ki=0.16 nM一致），10 nM抑制率>95%[2]
- 在原代人肝细胞中，瑞舒伐他汀钙（Rosuvastatin Calcium） （1~100 nM）浓度依赖性减少新生胆固醇合成：
- 10 nM 瑞舒伐他汀钙 使[14C]-乙酸掺入细胞胆固醇的量减少50%；
- 100 nM 瑞舒伐他汀钙 使胆固醇合成减少85%，且对细胞活力无显著影响（72小时MTT法检测活力>90%）[2]
- 阻断hERG电流与心脏复极：
- 在稳定表达hERG的HEK293细胞中，瑞舒伐他汀钙（Rosuvastatin Calcium） （5~50 μM）浓度依赖性抑制hERG钾电流（IhERG）：
- 15 μM 瑞舒伐他汀钙 使峰值IhERG减少50%（IC50=15 μM，全细胞膜片钳技术）；
- 20 μM 瑞舒伐他汀钙 使豚鼠心室肌细胞（离体）的90%复极动作电位时程（APD90）延长30%[3]
- 降低细胞膜上成熟hERG蛋白表达：
- 在稳定表达hERG的HEK293细胞中，瑞舒伐他汀钙（Rosuvastatin Calcium） （5~40 μM）处理48小时，浓度依赖性降低成熟hERG蛋白水平：
- 20 μM 瑞舒伐他汀钙 使成熟hERG蛋白（155 kDa）减少60%（Western blot），未成熟hERG（135 kDa）无变化；
- 40 μM 瑞舒伐他汀钙 使膜定位hERG减少75%（免疫荧光染色与细胞表面生物素化实验）；
- 机制：20 μM 瑞舒伐他汀钙 使成熟hERG的泛素化水平增加2.3倍（免疫共沉淀实验），促进其蛋白酶体降解[4]

在清醒且不受约束的豚鼠中，瑞舒伐他汀钙（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）持续两周可显着降低极低密度脂蛋白（VLDL）[4]。

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高胆固醇血症动物模型的降脂疗效：
1. 高脂饮食（HCD）喂养大鼠（雄性Sprague-Dawley大鼠，8周龄）：
- 大鼠随机分为4组（每组n=6）：溶剂组（0.5% CMC-Na）、瑞舒伐他汀钙（Rosuvastatin Calcium） 0.1 mg/kg/天组、1 mg/kg/天组、10 mg/kg/天组[2]
- 处理：每日口服灌胃，持续21天（期间继续饲喂HCD）；第21天采集禁食血清样本[2]
- 结果：
- 血清低密度脂蛋白胆固醇（LDL-C）：较溶剂组分别降低25%（0.1 mg/kg）、40%（1 mg/kg）、65%（10 mg/kg）（溶剂组LDL-C：280±30 mg/dL）；
- 血清总胆固醇（TC）：较溶剂组分别降低20%（0.1 mg/kg）、35%（1 mg/kg）、55%（10 mg/kg）（溶剂组TC：350±40 mg/dL）；
- 血清高密度脂蛋白胆固醇（HDL-C）：1 mg/kg和10 mg/kg组较溶剂组分别升高10%和15%（溶剂组HDL-C：45±5 mg/dL）[2]
2. LDL受体缺陷（LDLR-/-）小鼠（雄性，10周龄）：
- 口服瑞舒伐他汀钙（Rosuvastatin Calcium） 10 mg/kg/天，持续14天，血清LDL-C较溶剂组降低50%，TC降低45%[2]

重组人HMG-CoA还原酶活性检测：
反应体系（200 μL）包含50 mM Tris-HCl（pH 7.4）、5 mM MgCl2、2 mM DTT、100 nM重组人HMG-CoA还原酶、10 μM [14C]-HMG-CoA（底物）、200 μM NADPH（辅酶）及瑞舒伐他汀钙（Rosuvastatin Calcium） （0.01~10 nM）。37°C孵育60分钟后，加入50 μL 1 M HCl终止反应，95°C加热10分钟将产物甲羟戊酸转化为甲羟戊酸内酯。用乙酸乙酯提取甲羟戊酸内酯，液体闪烁计数器检测有机相[14C]-甲羟戊酸内酯的放射性。与溶剂组比较计算抑制率，通过双倒数作图法（改变[14C]-HMG-CoA浓度：2~20 μM）计算Ki[2]
- hERG电流检测：
将稳定表达hERG的HEK293细胞培养在玻璃盖玻片上，37°C下采用全细胞膜片钳技术记录电流。细胞外液成分（mM）：NaCl 140、KCl 4、CaCl2 1.8、MgCl2 1、HEPES 10（pH 7.4）；电极内液成分（mM）：KCl 130、MgATP 5、EGTA 5、HEPES 10（pH 7.2）。将瑞舒伐他汀钙（Rosuvastatin Calcium） （5~50 μM）加入细胞外液，通过电压 protocol（从-80 mV静息电位去极化至+40 mV持续2秒，再复极化至-50 mV持续5秒）诱发hERG电流（IhERG）。在-50 mV处测量电流振幅，拟合浓度-抑制曲线计算IC50[3]

人肝细胞胆固醇合成实验：
1. 细胞培养：原代人肝细胞以1×105细胞/孔接种于6孔板，在含10% FBS、100 U/mL青霉素和100 μg/mL链霉素的William’s E培养基中，37°C、5% CO2培养24小时[2]
2. 药物处理：更换为含瑞舒伐他汀钙（Rosuvastatin Calcium） （1~100 nM）或溶剂（0.1% DMSO）的无血清William’s E培养基，预孵育1小时后，每孔加入1 μCi/mL [14C]-乙酸，继续孵育24小时[2]
3. 胆固醇定量：细胞用冰浴PBS洗涤2次，0.1 M NaOH裂解，氯仿:甲醇（2:1，v/v）提取脂质。通过薄层色谱（TLC）分离胆固醇，液体闪烁计数器检测[14C]-胆固醇的放射性进行定量[2]
- hERG蛋白表达与定位实验：
1. 细胞培养：稳定表达hERG的HEK293细胞以2×105细胞/孔接种于6孔板（或玻璃盖玻片用于免疫荧光），在含10% FBS的DMEM培养基中培养24小时[4]
2. 药物处理：加入瑞舒伐他汀钙（Rosuvastatin Calcium） （5~40 μM），孵育48小时；蛋白酶体抑制实验中，细胞同时加入10 μM MG132（蛋白酶体抑制剂）[4]
3. Western blot：含蛋白酶抑制剂的RIPA缓冲液裂解细胞，30 μg蛋白经8% SDS-PAGE分离后转移至PVDF膜，加入抗hERG抗体（识别成熟155 kDa和未成熟135 kDa形式）和抗β-肌动蛋白抗体（内参）孵育，ImageJ定量条带强度[4]
4. 细胞表面生物素化：用sulfo-NHS-SS-生物素标记细胞表面蛋白，链霉亲和素-琼脂糖珠沉淀蛋白，Western blot检测hERG以定量膜定位hERG[4]
5. 免疫荧光：盖玻片上的细胞用4%多聚甲醛固定，0.1% Triton X-100透化，加入抗hERG抗体（Alexa Fluor 488标记二抗）和DAPI（染核）染色，共聚焦显微镜成像评估hERG定位[4]

20 mg/kg/day
Male beagle dogs and Monkey

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HCD-fed hypercholesterolemic rat study :
1. Animals: Male Sprague-Dawley rats (8 weeks old, 250–300 g) were housed under controlled conditions (22±2°C, 12-hour light/dark cycle) and fed a HCD (2% cholesterol, 10% lard) for 2 weeks to induce hypercholesterolemia [2]
2. Grouping: Rats were randomized into 4 groups (n=6/group):
- Vehicle group: 0.5% carboxymethyl cellulose sodium (CMC-Na) solution;
- Rosuvastatin Calcium 0.1 mg/kg/day group;
- Rosuvastatin Calcium 1 mg/kg/day group;
- Rosuvastatin Calcium 10 mg/kg/day group [2]
3. Drug preparation: Rosuvastatin Calcium was dissolved in 0.5% CMC-Na, sonicated for 5 minutes to form a homogeneous suspension [2]
4. Administration: Daily oral gavage at a volume of 10 mL/kg for 21 days (rats continued on HCD during treatment). Rats were fasted for 6 hours before sample collection on day 21 [2]
5. Sample collection and detection: Fasting serum was collected via orbital sinus puncture, and serum lipids (LDL-C, TC, HDL-C) were quantified via enzymatic kits [2]

Oral absorption :
- Healthy volunteers: Single oral dose of Rosuvastatin Calcium 20 mg showed oral bioavailability (F) = 20% (low bioavailability due to first-pass metabolism in the liver); time to reach maximum concentration (Tmax) = 3 hours; maximum plasma concentration (Cmax) = 37 ng/mL [2]
- Distribution :
- Tissue distribution: High concentration in the liver (target organ) — 2 hours after oral 20 mg in humans, liver concentration was 100-fold higher than plasma concentration;
- Volume of distribution (Vd) = 134 L (healthy volunteers, oral 20 mg) [2]
- Metabolism :
- Minimally metabolized in the liver: Only 10% of the dose is metabolized, primarily via cytochrome P450 (CYP) 2C9 and 2C19; no significant metabolism via CYP3A4 (reducing drug-drug interaction risk) [2]
- Elimination :
- Elimination half-life (t1/2) = 19 hours (healthy volunteers, oral 20 mg);
- Excretion: 90% of the dose is excreted via feces (60% as unchanged drug, 30% as metabolites), and 10% via urine [2]

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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In vitro cytotoxicity:
- Primary human hepatocytes and HEK293 cells: Rosuvastatin Calcium (up to 100 nM for hepatocytes, 40 μM for HEK293 cells) showed no significant cytotoxicity, with cell viability >90% compared to vehicle (MTT assay, 72-hour treatment) [2][4]
- Cardiac toxicity (hERG-related):
- In vitro: 15 μM Rosuvastatin Calcium inhibited hERG current by 50%, and 20 μM prolonged guinea pig ventricular myocyte APD90 by 30%, indicating potential risk of QT interval prolongation (a cardiac arrhythmia risk factor) [3]
- In vivo safety :
- HCD-fed rats (10 mg/kg/day, 21 days):
- No significant changes in body weight (weight change <5% vs. vehicle);
- Serum liver function markers (ALT, AST) were slightly increased (1.2-fold vs. vehicle, within normal upper limit);
- Serum creatinine and BUN (kidney function markers) remained normal;
- No clinical signs of toxicity (e.g., lethargy, diarrhea) [2]
- Plasma protein binding :
- Human plasma: Protein binding rate = 90% (equilibrium dialysis, 37°C, pH 7.4) [2]

[1]. Watanabe, M., et al., 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]. Carswell C.I., et al. Rosuvastatin. Drugs, 2002. 62(14): p. 2075-85; discussion 2086-7.
[3]. Plante I, et al. Rosuvastatin blocks hERG current and prolongs cardiac repolarization. J Pharm Sci. 2012 Feb;101(2):868-78.
[4]. Feng PF, et al. Intracellular Mechanism of Rosuvastatin-Induced Decrease in Mature hERG Protein Expression on Membrane. Mol Pharm. 2019 Apr 1;16(4):1477-1488.

Rosuvastatin calcium is an organic calcium salt that is the hemicalcium salt of rosuvastatin. It has a role as an anti-inflammatory agent, a CETP inhibitor and a cardioprotective agent. It is an organic calcium salt and a N-acyl-15-methylhexadecasphinganine-1-phosphoethanolamine. It contains a rosuvastatin(1-).
Rosuvastatin Calcium is the calcium salt form of rosuvastatin, a statin with antilipidemic activity. Rosuvastatin selectively and competitively binds to and inhibits hepatic hydroxymethyl-glutaryl coenzyme A (HMG-CoA) reductase, the enzyme which catalyzes the conversion of HMG-CoA to mevalonate, a precursor of cholesterol. This leads to a decrease in hepatic cholesterol levels and increase in uptake of LDL cholesterol.
A HYDROXYMETHYLGLUTARYL-COA-REDUCTASE INHIBITOR, or statin, that reduces the plasma concentrations of LDL-CHOLESTEROL; APOLIPOPROTEIN B, and TRIGLYCERIDES while increasing HDL-CHOLESTEROL levels in patients with HYPERCHOLESTEROLEMIA and those at risk for CARDIOVASCULAR DISEASES.
See also: Rosuvastatin (has active moiety); Ezetimibe; rosuvastatin calcium (component of).

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Drug Indication
Homozygous Familial Hypercholesterolaemia, Prevention of cardiovascular events, Primary combined (mixed) dyslipidaemia, Primary hypercholesterolaemia

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Rosuvastatin Calcium is a synthetic, lipid-lowering agent belonging to the statin class, clinically approved for the treatment of hypercholesterolemia (elevated LDL-C) and prevention of atherosclerotic cardiovascular disease (ASCVD, e.g., myocardial infarction, stroke) [2]
- Core lipid-lowering mechanism: Inhibits HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis (converts HMG-CoA to mevalonate). Reduced mevalonate production decreases de novo cholesterol synthesis in the liver, triggering upregulation of LDL receptors on hepatocyte membranes, which increases LDL-C clearance from the bloodstream [2]
- Cardiac safety consideration: Rosuvastatin Calcium inhibits hERG potassium channels (critical for cardiac repolarization), potentially prolonging the QT interval and increasing arrhythmia risk. However, clinical studies show this risk is low at therapeutic doses (plasma concentrations ~10–50 ng/mL, far below the in vitro hERG IC50=15 μM) [3]
- Pharmacokinetic advantage: Minimally metabolized by CYP3A4 (a major drug-metabolizing enzyme), reducing interactions with CYP3A4 substrates (e.g., some antibiotics, antifungals) compared to other statins (e.g., simvastatin) [2]
- Literature [1] focuses on the synthesis and activity of a novel series of HMG-CoA reductase inhibitors (methanesulfonamide-substituted 3,5-dihydroxy-6-heptenoates) and does not involve Rosuvastatin Calcium [1]

C22H28FN3O6S.1/2CA

500.57

1000.283

147098-20-2

Rosuvastatin Sodium;147098-18-8;Rosuvastatin-d3 sodium;1279031-70-7;Rosuvastatin Calcium (Standard);147098-20-2;Rosuvastatin;287714-41-4;Rosuvastatin-d3;1133429-16-9;Rosuvastatin-d6 sodium;2070009-41-3;Rosuvastatin-d6 calcium

5282455

White to off-white solid powder

745.6ºC at 760 mmHg

122ºC

404.7ºC

4.295

304.26

4

20

18

67

761

4

CC(C1=NC(=NC(=C1/C=C/[C@@H](O)C[C@@H](O)CC(=O)[O-])C2=CC=C(C=C2)F)N(S(=O)(=O)C)C)C.CC(C1=NC(=NC(=C1/C=C/[C@@H](O)C[C@@H](O)CC(=O)[O-])C2=CC=C(C=C2)F)N(S(=O)(=O)C)C)C.[Ca+2]

LALFOYNTGMUKGG-BGRFNVSISA-L

InChI=1S/2C22H28FN3O6S.Ca/c2*1-13(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;/h2*5-10,13,16-17,27-28H,11-12H2,1-4H3,(H,29,30);/q;;+2/p-2/b2*10-9+;/t2*16-,17-;/m11./s1

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

ZD 4522; Rosuvastatin calcium; S-4522; Rosuvastatin hemicalcium; ZD-4522; ZD4522; S 4522; S4522; ZD 4522 calcium salt; ZD 4522 Calcium; 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

注意： 请将本产品存放在密封且受保护的环境中，避免吸湿/受潮。

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

配方 1 中的溶解度: ≥ 2.08 mg/mL (4.16 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.08 mg/mL (4.16 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.08 mg/mL (4.16 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL 澄清 DMSO 储备液添加到 900 μL 玉米油中并混合均匀。

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配方 4 中的溶解度: 4% DMSO+30% PEG 300+dd H2O:10 mg/mL

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。