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]

In vitro activity: Rosuvastatin is relatively hydrophilic and is highly selective for hepatic cells; its uptake is mediated by the liver-specific organic anion transporter OATP-C. Rosuvastatin is a high-affinity substrate for OATP-C with apparent association constant of 8.5 μM. Rosuvastatin inhibits cholesterol biosynthesis in rat liver isolated hepatocytes with IC50 of 1.12 nM. Rosuvastatin causes approximately 10 times greater increase of mRNA of LDL receptors than pravastatin. Rosuvastatin (100 μM) decreases the extent of U937 adhesion to TNF-α-stimulated HUVEC. Rosuvastatin inhibits the expressions of ICAM-1, MCP-1, IL-8, IL-6, and COX-2 mRNA and protein levels through inhibition of c-Jun N-terminal kinase and nuclear factor-kB in endothelial cells.

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Kinase Assay: Rosuvastatin Calcium is a competitive inhibitor of HMG-CoA reductase with IC50 of 11 nM.

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Cell Assay: Rosuvastatin is relatively hydrophilic and is highly selective for hepatic cells; its uptake is mediated by the liver-specific organic anion transporter OATP-C. Rosuvastatin is a high-affinity substrate for OATP-C with apparent association constant of 8.5 μM. Rosuvastatin inhibits cholesterol biosynthesis in rat liver isolated hepatocytes with IC50 of 1.12 nM. Rosuvastatin causes approximately 10 times greater increase of mRNA of LDL receptors than pravastatin. Rosuvastatin (100 μM) decreases the extent of U937 adhesion to TNF-α-stimulated HUVEC. Rosuvastatin inhibits the expressions of ICAM-1, MCP-1, IL-8, IL-6, and COX-2 mRNA and protein levels through inhibition of c-Jun N-terminal kinase and nuclear factor-kB in endothelial cells.

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1. Rosuvastatin (3a, S-4522) potently inhibits HMG-CoA reductase activity in vitro with an IC₅₀ of 11 nM, which is approximately four times more potent than lovastatin sodium salt; in rat isolated hepatocytes, it inhibits cholesterol biosynthesis with an IC₅₀ of 1.12 nM, showing ~100-fold higher potency than pravastatin [1]
2. In hERG-transfected HEK293 cells, Rosuvastatin blocks hERG current with an IC₅₀ of 195 nM; the hERG blockade is modulated by the coexpression of efflux transporters (BCRP, MDR1) and influx transporter (OATP2B1) [2]
3. In human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), Rosuvastatin accelerates hERG channel inactivation, reduces hERG current amplitude, and prolongs the action potential duration (APD); it also decreases the expression of mature hERG protein on the cell membrane, downregulates hERG mRNA expression via transcription factor Sp1 (verified by Sp1 siRNA and agonist epicatechin), and reduces the interaction between heat shock protein 70 (Hsp70) and hERG protein (disrupting hERG folding) [3]
4. Rosuvastatin activates ATF6 (a key mediator of the unfolded protein response, UPR), upregulates the expression of molecular chaperones calnexin and calreticulin (involved in channel folding); the degradation of hERG channels is mediated by both lysosomal and proteasomal pathways in hiPSC-CMs [3]
5. In isolated guinea pig hearts, 195 nM Rosuvastatin prolongs the monophasic action potential duration at 90% repolarization (MAPD₉₀) by 11 ± 1 ms (basic cycle length of 250 ms, p < 0.05) [2]

In awake and unrestrained guinea pigs, rosuvastatin (10 mg/kg, intraperitoneal) prolongs QTc from 201±1 to 210±2 ms[2]. In diabetic mellitus rats generated by streptozocin, rosuvastatin (20 mg/kg/day) significantly lowers very low-density lipoproteins (VLDL)[4].

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1. In conscious and unrestrained guinea pigs, intraperitoneal administration of Rosuvastatin (10 mg/kg) prolongs the corrected QT interval (QTc) from 201 ± 1 ms to 210 ± 2 ms (p < 0.05) [2]
2. In clinical trials of hypercholesterolemia patients (6–52 weeks’ duration), Rosuvastatin is superior to atorvastatin, simvastatin, and pravastatin in improving lipid profiles; in a 1-year dose-titration study, Rosuvastatin (mean dose 13.4 mg/day) enabled 98% of patients to achieve NCEP LDL-cholesterol targets, compared with 87% of atorvastatin recipients (mean dose 20.8 mg/day), with a more significant difference in high-risk patients (97% vs 61%) [4]
3. In another 1-year clinical trial, 88% of Rosuvastatin recipients (mean doses 9.5/13.8 mg/day) achieved NCEP LDL-cholesterol targets, compared with 60% of pravastatin (20 mg/day) and 73% of simvastatin (20 mg/day) recipients; the difference was more pronounced in high-risk patients [4]
4. Rosuvastatin improves lipid profiles in patients with heterozygous/homozygous familial hypercholesterolemia, hypertriglyceridemia, or mixed dyslipidemias in clinical trials [4]

1. HMG-CoA Reductase Activity Assay: HMG-CoA reductase enzyme preparation was incubated with serial concentrations of Rosuvastatin (3a, S-4522) and substrate HMG-CoA under optimal reaction conditions (temperature, pH). The enzyme activity was evaluated by detecting the production of reaction products or consumption of substrates; dose-response curves were plotted to calculate the IC₅₀. Lovastatin sodium salt was used as a positive control to compare inhibitory potency [1]
2. hERG Channel Current Recording (Patch-Clamp Assay): hERG-transfected HEK293 cells were seeded and cultured to form adherent monolayers. Whole-cell patch-clamp technique was used with a specific voltage-clamp protocol (depolarization and repolarization pulses) to record hERG currents under different concentrations of Rosuvastatin. The amplitude of hERG currents was analyzed, dose-response curves were generated, and the IC₅₀ for hERG blockade was calculated. The ionic composition, osmolarity, and pH of extracellular and intracellular solutions were maintained stable [2]

1. Rat Primary Hepatocyte Cholesterol Synthesis Assay: Rat primary hepatocytes were isolated, seeded in culture plates, and cultured until adherent. Serial concentrations of Rosuvastatin were added, along with a radiolabeled precursor ([¹⁴C]acetate). After incubation, intracellular cholesterol was extracted, and radioactivity was measured by liquid scintillation counting to calculate the inhibition rate of cholesterol biosynthesis. Dose-response curves were plotted to determine the IC₅₀, with pravastatin as a control [1]
2. hERG-Transfected HEK293 Cell Functional Assay: hERG gene was transfected into HEK293 cells to establish stable expression cell lines. Different concentrations of Rosuvastatin were added to the cultured cells, and the effects of coexpressed transporters (BCRP, MDR1, OATP2B1) on hERG blockade were detected by patch-clamp recording of hERG currents. The correlation between transporter expression levels and the inhibitory effect of Rosuvastatin was analyzed; blank and solvent control groups were set to exclude non-specific effects [2]
3. hiPSC-CMs Electrophysiology and Protein Expression Assay: Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were cultured and treated with different concentrations of Rosuvastatin. Action potentials were recorded by patch-clamp to analyze changes in APD. Western blot was used to detect the expression of mature/immature hERG protein on the cell membrane, and RT-PCR was performed to measure hERG mRNA levels. Sp1 siRNA or agonist epicatechin was used to verify the role of Sp1 in hERG expression regulation. Co-immunoprecipitation was used to detect the interaction between Hsp70 and hERG, and Western blot was used to measure the expression of ATF6, calnexin, and calreticulin (to analyze UPR activation). Lysosomal and proteasomal inhibitors were used to treat cells, and changes in hERG degradation were detected to identify degradation pathways [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 the absorption rate was estimated at 50%, consistent with a significant first-pass effect after oral administration. Another study of healthy volunteers found that the peak plasma concentration (Cmax) of rosuvastatin was 6.06 ng/mL, with a median time to peak concentration of 5 hours after oral administration. Both Cmax and AUC increased approximately proportionally with the dose. Food or administration at different times of day did not show any effect on the AUC of rosuvastatin. Many statins are known to interact with hepatic uptake transporters, resulting in high concentrations at the 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, especially when CYP3A4 is involved in its metabolism. Pharmacogenetic studies have shown that the BCRP gene c.421C>A single nucleotide polymorphism (SNP) is associated with rosuvastatin. Individuals carrying the 421AA genotype exhibited reduced functional activity of rosuvastatin, with AUC and Cmax values 2.4 times higher than those of controls carrying the 421CC genotype. This is significant for individual differences in drug efficacy and toxicity, particularly noteworthy given the higher prevalence of the BCRP c.421C>A polymorphism in Asian populations compared to Caucasians. Other statins affected by this polymorphism include fluvastatin and atorvastatin. Furthermore, genetic differences in the hepatic organic anion transporter 1B1 (OATP1B1) have also been shown to affect the pharmacokinetics of rosuvastatin. Pharmacogenetic studies have shown that homozygous individuals with the c.521T>C SNP had a 1.62-fold increased AUC of rosuvastatin compared to homozygous individuals with the 521TT SNP. Other statins affected by this polymorphism include simvastatin, pitavastatin, atorvastatin, and pravastatin. For patients known to carry the c.421AA BCRP or c.521CC OATP1B1 genotypes, a maximum daily dose of rosuvastatin is recommended to avoid the risk of adverse reactions due to increased drug exposure, such as muscle pain and rhabdomyolysis. Rosuvastatin is not extensively metabolized; approximately 10% of the radiolabeled dose is recovered as metabolites. After oral administration, rosuvastatin and its metabolites are primarily excreted in feces (90%). After intravenous administration, approximately 28% of the drug is cleared by the kidneys and 72% by the liver. A study in healthy adult male volunteers found that within 72 hours of administration, approximately 90% of the rosuvastatin dose was excreted in feces, with the remaining 10% excreted in urine. After 10 days of administration, the drug was completely eliminated from the body. The study also found that approximately 76.8% of the excreted dose was the unchanged drug, with the remainder excreted as the metabolites N-desmethylrosuvastatin and rosuvastatin-5S-lactone. Renal tubular secretion accounts for over 90% of total renal clearance, primarily mediated by the uptake transporter OAT3 (organic anion transporter 1), while the role of OAT1 is minimal. Rosuvastatin undergoes a first-pass effect in the liver, the primary site of cholesterol synthesis and low-density lipoprotein cholesterol (LDL-C) clearance. The mean volume of distribution of rosuvastatin at steady state is approximately 134 liters. In human clinical pharmacology studies, peak plasma concentrations are reached 3 to 5 hours after oral administration of rosuvastatin. Both Cmax and AUC increase approximately proportionally with the dose of rosuvastatin. The absolute bioavailability of rosuvastatin is approximately 20%. Co-administration of rosuvastatin with food does not affect its AUC. The AUC of rosuvastatin is not different after administration in the morning or evening. The mean volume of distribution of rosuvastatin at steady state is approximately 134 liters. Rosuvastatin binds to plasma proteins at a rate of 88%, primarily albumin. This binding is reversible and independent of plasma concentration. After oral administration, rosuvastatin and its metabolites are primarily excreted in feces (90%). After intravenous administration, approximately 28% of the drug is cleared by the kidneys and 72% by the liver. /Breast Milk/ Limited data indicate that rosuvastatin is present in human breast milk. For more complete data on the absorption, distribution, and excretion of rosuvastatin (7 items), please visit the HSDB record page.

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Metabolism/Metabolites
The metabolism of rosuvastatin is not extensive, as evidenced by the fact that only a small amount (approximately 10%) of radiolabeled doses is recovered as metabolites. Cytochrome P450 (CYP) 2C9 is primarily responsible for generating the major metabolite of rosuvastatin, N-desmethylrosuvastatin, which has approximately 20-50% of the in vitro pharmacological activity of the parent compound. However, since no significant effect on the pharmacokinetics of rosuvastatin was observed when it was co-administered with the potent CYP2C9 inhibitor fluconazole, this metabolic pathway is considered clinically insignificant. In vitro and in vivo data indicate that rosuvastatin has no clinically significant interaction with cytochrome P450 (as a substrate, inhibitor, or inducer). Therefore, the likelihood of drug interactions when co-administered with drugs metabolized by cytochrome P450 is very low. Rosuvastatin is not extensively metabolized; approximately 10% of the radiolabeled dose is recovered as metabolites. The major metabolite is N-desmethylrosuvastatin, primarily generated by cytochrome P450 2C9. In vitro studies have shown that the HMG-CoA reductase inhibitory activity of N-desmethylrosuvastatin is approximately one-sixth to one-half that of the parent compound. Overall, over 90% of the plasma active HMG-CoA reductase inhibitory activity originates from the parent compound. Metabolism is not extensive. Only about 10% is excreted as metabolites. Cytochrome P450 (CYP) 2C9 is the main enzyme responsible for the formation of N-desmethylrosuvastatin, the major metabolite of rosuvastatin. In vitro studies have shown that the pharmacological activity of N-desmethylrosuvastatin is approximately 50% of that of its parent compound. Clinically, the clearance of rosuvastatin is not dependent on cytochrome P450 3A4 metabolism. Rosuvastatin accounts for over 90% of its pharmacological action. CYP2C9 inhibitors increase the AUC by less than 2-fold. This interaction appears to be clinically insignificant. Elimination pathways: Rosuvastatin is not extensively metabolized; approximately 10% of the radiolabeled dose is recovered as metabolites. After oral administration, rosuvastatin and its metabolites are primarily excreted in the feces (90%). After intravenous administration, approximately 28% of systemic clearance occurs via the kidneys and 72% via the liver.
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 dose.
The elimination half-life of rosuvastatin is approximately 19 hours.

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1. Rosuvastatinis not widely metabolized and has a low tendency for drug interactions;[4]

Toxicity Summary
Identification and Uses: Rosuvastatin is a hydroxymethylglutaryl-CoA reductase inhibitor. It is indicated for reducing the risk of stroke, myocardial infarction, and arterial revascularization surgery. Human Exposure and Toxicity: Rosuvastatin is currently the most effective commercially available 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, used to lower LDL cholesterol. Rosuvastatin is associated with a variety of adverse reactions, including rhabdomyolysis and arthralgia. Myopathy and rhabdomyolysis have been reported in patients taking statins, including rosuvastatin, with acute renal failure secondary to myoglobinuria. These adverse reactions can occur at any dose, but the risk increases with the highest dose of rosuvastatin (40 mg daily). There have been reports of delayed rhabdomyolysis, inducing Takotsubo cardiomyopathy, in patients with long-term rosuvastatin use, without any prior stress factors or changes in patient health, accompanied by nonspecific muscle-related symptoms. A case of acute rhabdomyolysis during a race was reported in the literature, occurring while a marathon runner was taking rosuvastatin. A 77-year-old patient developed acute pancreatitis after taking rosuvastatin, with symptoms resolving upon discontinuation of the drug. Rare post-marketing reports of fatal and non-fatal hepatic failure in patients taking statins, including rosuvastatin, have been documented. The genotoxicity of rosuvastatin has been assessed using DNA damage detection via chromosomal aberration (CA), micronucleus (MN), and comet assays on human peripheral blood lymphocytes. Based on these results, rosuvastatin exhibits cytotoxicity and chromosome breakage/aneuploidy-inducing effects on human peripheral blood lymphocytes. Animal studies: Acute toxicity was low in rats and dogs following single oral and intravenous administration of rosuvastatin. No deaths occurred in rats after oral administration of 1000 mg/kg or 2000 mg/kg doses, and no other treatment-related adverse reactions were observed in either dose group except for weight loss in the 2000 mg/kg dose group. Following oral administration of 1000 mg/kg or 2000 mg/kg to dogs, the primary clinical manifestation was vomiting on the day of administration, a symptom observed in both male and female dogs. In a 104-week rat carcinogenicity study, doses of 2, 20, 60, or 80 mg/kg/day were administered. Results showed that only female rats in the 80 mg/kg/day dose group exhibited a significantly increased incidence of uterine polyps. In a 107-week mouse carcinogenicity study, doses of 10, 60, 200, or 400 mg/kg/day were administered. The 400 mg/kg/day dose group showed poor tolerability, leading to early termination of the study in this dose group. An increased incidence of hepatocellular carcinoma was observed in the 200 mg/kg/day dose group, and an increased incidence of hepatocellular adenoma was observed in the 60 and 200 mg/kg/day dose groups. Rosuvastatin did not show teratogenic effects in rats at doses ≤25 mg/kg/day or rabbits at doses ≤3 mg/kg/day. In vitro experiments showed that, regardless of metabolic activation, rosuvastatin did not exhibit mutagenicity or chromosomal breakage in the Ames test for Salmonella and Escherichia coli, the L-5178 y +/- mouse lymphoma assay, or the Chinese hamster lung cell chromosomal aberration assay. In vivo mouse micronucleus assays were also negative. Rosuvastatin is a competitive inhibitor of HMG-CoA reductase. HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonate, a rate-limiting step in the early stages of cholesterol biosynthesis. Rosuvastatin primarily acts on the liver. Decreased hepatic cholesterol concentration stimulates the upregulation of hepatic low-density lipoprotein (LDL) receptors, thereby increasing hepatic LDL uptake. Rosuvastatin also inhibits the synthesis of very low-density lipoprotein (VLDL) in the liver. Overall, rosuvastatin reduces plasma LDL and VLDL levels. In vitro and in vivo animal studies have also demonstrated that rosuvastatin possesses vasoprotective effects independent of its lipid-lowering properties. Rosuvastatin exerts an anti-inflammatory effect on the rat mesenteric microvascular endothelium by attenuating leukocyte rolling, adhesion, and transendothelial migration (A2814). The drug also modulates nitric oxide synthase (NOS) expression and alleviates ischemia-reperfusion injury in the rat heart (A2818). Rosuvastatin enhances nitric oxide bioavailability by upregulating NOS (A2816) and increasing NOS stability through posttranscriptional polyadenylation (A7824) (A2814, 12031849, 15914111). How rosuvastatin produces these effects is currently unclear, but it may be related to decreased mevalonate concentrations.
Hepatotoxicity
Rosuvastatin treatment is associated with mild, asymptomatic, and usually transient elevations in serum transaminases in 1% to 3% of patients. In patients receiving rosuvastatin, the incidence of ALT levels exceeding three times the upper limit of normal (1.1%) was slightly higher than in the placebo group (0.5%). Elevated serum enzymes were more common with high-dose rosuvastatin treatment, occurring in 2.2% at 40 mg daily. Most of these elevations were self-limiting and required no dose adjustment. Rosuvastatin has also been associated with significant, clinically observable liver injury, but this is rare, occurring in less than 1 in 10,000 cases. Symptoms usually appear 2 to 4 months after starting treatment, and the pattern of elevated serum enzymes is typically hepatocellular, although cholestatic cases have also been reported. Rash, fever, and eosinophilia are uncommon. Several statins, including rosuvastatin, have been associated with hepatitis with autoimmune characteristics, characterized by positive antinuclear antibodies (ANA), elevated serum immunoglobulin levels, and a clinical response to corticosteroids. However, these characteristics are not always present (Case 1). This damage is usually self-limiting, and the damage resolves rapidly once rosuvastatin is discontinued. However, it can also be severe, and there have been reports of fatal cases.
Probability Score: A (Possibly the cause of clinically significant liver damage).

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Effects during Pregnancy and Lactation
◉ Overview of Use During Lactation
Rosuvastatin concentrations in breast milk are very low, but there is currently no published information regarding its use during lactation. It is generally believed that women taking statins should not breastfeed due to concerns about disrupting the infant's lipid metabolism. However, some argue that children homozygous for familial hypercholesterolemia who have started statin treatment from age 1, and whose oral bioavailability is low, pose a lower risk to breastfed infants, especially rosuvastatin and pravastatin. Until more data are available, alternative medications are preferable, especially when breastfeeding newborns or premature infants.
◉ Effects on Breastfed Infants
No published information found as of the revision date.
◉ Effects on Lactation and Breast Milk
There have been case reports of rosuvastatin potentially inducing gynecomastia in men. Serum prolactin levels were not measured.

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Protein Binding
Rosuvastatin binds to plasma proteins at a rate of 88%, primarily albumin. This binding is reversible and independent of plasma concentration.

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Interactions
Concomitant use of rosuvastatin with ritonavir-enhanced teplanavir has little effect on rosuvastatin exposure. Concomitant use of rosuvastatin (single dose 10 mg) with ritonavir-enhanced teplanavir (teplanavir 500 mg, ritonavir 200 mg, twice daily for 11 days) resulted in a two-fold increase in peak plasma concentration and a 26% increase in AUC of rosuvastatin. Therefore, caution should be exercised when using rosuvastatin concomitantly with ritonavir-enhanced teplanavir.
Concomitant use of rosuvastatin with lipid-lowering doses (1 g or higher daily) of niacin may increase the risk of myopathy. Data from multiple large randomized studies have shown that concomitant use of niacin (1.5–2 g daily) with another statin (e.g., simvastatin 40–80 mg once daily, with or without ezetimibe) increases the risk of serious adverse reactions, including glycemic instability (requiring hospitalization), diabetes, gastrointestinal adverse reactions, myopathy, gout, rash, skin ulcers, infection, and bleeding. Caution should be exercised when rosuvastatin is used concomitantly with lipid-lowering doses of niacin.
Concomitant use of rosuvastatin (20 mg once daily) with locitapape (10 mg once daily for 7 days) increased the peak plasma concentration and AUC of rosuvastatin by 6% and 2%, respectively. Concomitant administration of rosuvastatin (20 mg once daily) and lomistatin (60 mg once daily for 7 days) increased peak plasma concentration and AUC of rosuvastatin by 4% and 32%, respectively. No dose adjustment of rosuvastatin is required when used with lomistatin. Concomitant administration of rosuvastatin (80 mg once daily) and ketoconazole (200 mg twice daily for 7 days) decreased peak plasma concentration of rosuvastatin by 5% and increased AUC by 2%. For more complete data on drug interactions of rosuvastatin (25 items in total), please visit the HSDB records page. 1. Rosuvastatin blocks hERG currents, which are associated with an increased risk of long QT syndrome (LQTS); BCRP, MDR1, and OATP2B1 gene polymorphisms may further increase the risk of LQTS in some patients after taking rosuvastatin [2]. 2. Rosuvastatin delays cardiac repolarization by reducing the expression and function of hERG channels, which may induce LQTS, torsades de pointes, and sudden death; no significant cytotoxicity (e.g., increased apoptosis) was observed in cell experiments, but abnormal hERG channels can lead to cardiac electrophysiological disturbances [3]. 3. Rosuvastatin was well tolerated in clinical trials lasting up to 1 year; no serious 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 that indexes human clinical studies funded by public and private institutions worldwide. The website is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each record on ClinicalTrials.gov includes a summary of the study protocol, including: the disease or condition; the intervention (e.g., the medical product, behavior, or procedure under investigation); the title, description, and design of the study; participation requirements (eligibility criteria); the location of the study; contact information for the study location; and links to relevant information from other health websites, such as the NLM's MedlinePlus (for providing patient health information) and PubMed (for providing citations and abstracts of academic articles in the medical field). Rosuvastatin is indexed in the database. For individuals with asymptomatic coronary artery disease but assessed as having increased cardiovascular disease risk based on age (≥50 years for men, ≥60 years for women), high-sensitivity C-reactive protein (hsCRP) ≥2 mg/L, and at least one other cardiovascular disease risk factor (such as hypertension, low high-density lipoprotein cholesterol, smoking, or a family history of early-onset coronary artery disease), rosuvastatin (Crestor) is indicated for: reducing the risk of stroke, reducing the risk of myocardial infarction, and reducing the risk of arterial revascularization surgery. (This information is included on the US product label.)
Rosuvastatin (Crestor) is indicated as adjunctive therapy to dietary therapy to slow the progression of atherosclerosis in adult patients as part of a treatment strategy to lower total cholesterol and low-density lipoprotein cholesterol to target levels. /This information is included on the US product label./
For more complete data on the therapeutic uses of rosuvastatin (11 types), please visit the HSDB record page.

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Drug Warning
Rosuvastatin is contraindicated in pregnant women because its safety in pregnant women has not been established and there is no clear benefit to its use during pregnancy. Because HMG-CoA reductase inhibitors reduce cholesterol synthesis and may reduce the synthesis of other cholesterol-derived bioactive substances, rosuvastatin use in pregnant women may harm the fetus. Rosuvastatin should be discontinued immediately upon confirmation of pregnancy.

Rosuvastatin should be prescribed with caution in patients with predisposing factors for myopathy (e.g., age ≥65 years, inadequate treatment of hypothyroidism, renal impairment).

Acute renal failure due to myopathy and rhabdomyolysis with myoglobinuria has been reported in patients taking statins (including rosuvastatin). These adverse reactions can occur at any dose, but the risk is higher with the highest dose of rosuvastatin (40 mg daily).

Immune-mediated necrotizing myopathy (IMNM) is an autoimmune myopathy that has been rarely reported in patients taking statins. IMN is characterized by proximal muscle weakness and elevated creatine kinase (CK, creatine phosphokinase, CPK) levels that persist even after discontinuation of statin therapy; necrotizing myopathy without significant inflammation; and improvement following immunosuppressive therapy.
For more complete data on drug warnings for rosuvastatin (22 total), please visit the HSDB records page.
Pharmacodynamics

Rosuvastatin is a synthetic, enantiomerically pure lipid-lowering drug. It is used to lower plasma levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (apoB), non-high-density lipoprotein cholesterol (non-HDL-C), and triglycerides (TG), while increasing high-density lipoprotein cholesterol (HDL-C). High LDL-C, low HDL-C, and high TG concentrations in plasma are associated with an increased risk of atherosclerosis and cardiovascular disease. The ratio of total cholesterol to HDL-C is a strong predictor of coronary artery disease, with a high ratio associated with a higher risk. Elevated HDL-C levels are associated with a reduced cardiovascular risk. Rosuvastatin reduces the incidence and mortality of cardiovascular disease by lowering LDL-C and TG and raising HDL-C. Elevated cholesterol levels, especially elevated low-density lipoprotein cholesterol (LDL), are a significant risk factor for cardiovascular disease. Multiple landmark studies have demonstrated that using statins to lower LDL-C levels significantly reduces the risk of cardiovascular disease (CVD) and all-cause mortality. Because statins can reduce all-cause mortality, including fatal and non-fatal CVD, and decrease the need for revascularization or angioplasty after a heart attack, they are considered a cost-effective CVD treatment option. Evidence suggests that even in low-risk individuals (with a 5-year risk of major vascular events <10%), statins can reduce the relative risk of major cardiovascular events (heart attack, stroke, coronary revascularization, and coronary death) by 20%-22% for every 1 mmol/L reduction in LDL-C, without significant side effects or risks. Skeletal Muscle Effects HMG-CoA reductase inhibitors (including rosuvastatin) have been reported to cause myopathy and rhabdomyolysis, leading to secondary myoglobinuria and acute renal failure. These risks may occur at any dose level, but are higher at the highest dose (40 mg). Rosuvastatin should be used with caution in patients with predisposing factors for myopathy (e.g., age ≥65 years, inadequate treatment of hypothyroidism, or renal impairment). The risk of myopathy may increase if taken concurrently with other lipid-lowering drugs (such as fenofibrate or niacin), gemfibrozil, cyclosporine, atazanavir/ritonavir, lopinavir/ritonavir, or simeprevir during rosuvastatin treatment. There have been reports of myopathy, including rhabdomyolysis, occurring when HMG-CoA reductase inhibitors (including rosuvastatin) are used in combination with colchicine; therefore, caution should be exercised when taking these two drugs concurrently. Real-world data from observational studies show that 10-15% of patients taking statins may experience muscle soreness during treatment. Liver Enzyme Abnormalities Elevated serum transaminases have been reported in patients taking HMG-CoA reductase inhibitors (including rosuvastatin). In most cases, this elevation is transient and returns to normal or improves with continued treatment or a short break from the drug. Two cases of jaundice were reported, but their relationship to rosuvastatin treatment could not be determined; the jaundice subsided after discontinuation of the drug. No cases of liver failure or irreversible liver disease were observed in these trials. Endocrine Effects Elevated glycated hemoglobin (HbA1c) and fasting blood glucose levels have been reported in patients taking HMG-CoA reductase inhibitors (including rosuvastatin calcium). Based on clinical trial data for rosuvastatin, these elevations may exceed the diagnostic threshold for diabetes in some cases. An in vitro study found that atorvastatin, pravastatin, rosuvastatin, and pitavastatin exhibited dose-dependent cytotoxic effects on human pancreatic β-cells, reducing cell viability by 32%, 41%, 34%, and 29%, respectively, compared to the control group. Furthermore, insulin secretion rates were reduced by 34%, 30%, 27%, and 19%, respectively, compared to the control group. HMG-CoA reductase inhibitors interfere with cholesterol synthesis and lower cholesterol levels, and therefore theoretically may inhibit the production of adrenal or gonadal steroid hormones. Rosuvastatin had no effect on thyroid metabolism as assessed by non-stimulatory cortisol levels and thyroid-stimulating hormone (TSH) plasma concentrations. In patients treated with rosuvastatin, adrenal cortical reserves were not impaired, and plasma cortisol levels were not reduced. Clinical studies of other HMG-CoA reductase inhibitors have shown that these drugs do not reduce plasma testosterone levels. The effects of HMG-CoA reductase inhibitors on male fertility have not been investigated. Their effects on the pituitary-gonadal axis in premenopausal women (if any) are unclear. Cardiovascular Ubiquinone levels were not measured in clinical trials of rosuvastatin, but significant reductions in circulating ubiquinone levels have been observed in patients treated with other statins. The clinical significance of long-term statin use potentially leading to ubiquinone deficiency has not been established. There are reports that reduced myocardial ubiquinone levels may lead to impaired cardiac function in patients with borderline congestive heart failure. Lipoprotein A In some patients, the beneficial effects of reduced total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels may be partially diminished by simultaneous increases in lipoprotein(a) [Lp(a)] concentrations. Current knowledge suggests that high Lp(a) levels are an emerging risk factor for coronary artery disease. Therefore, for high-risk patients receiving rosuvastatin treatment, maintaining and enhancing lifestyle changes is desirable. Further studies have shown that the effect of statins on Lp(a) levels in patients with dyslipidemia depends on their apolipoprotein(a) phenotype; statins only increase Lp(a) levels in patients with the low molecular weight apolipoprotein(a) phenotype.

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1. Rosuvastatin (3a, S-4522) is a novel mesylate pyrimidine-substituted 3,5-dihydroxy-6-heptenoic acid ester and a potent HMG-CoA reductase inhibitor; due to its excellent inhibitory activity, rosuvastatin was selected as a lead compound from a series of analogues[1].
2. Rosuvastatin is a mesylate 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 the expression of hERG on the cell membrane through two pathways: interfering with the transport of immature hERG channels to the cell membrane and promoting the degradation of mature hERG channels[3]. 4. Rosuvastatin is suitable for the treatment of dyslipidemia; clinical trials have shown that its lipid-lowering efficacy is superior to that of atorvastatin, simvastatin and pravastatin, especially in patients with high-risk hypercholesterolemia[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

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)