|Rosuvastatin calcium Chemical Properties|
|Rosuvastatin calcium Usage And Synthesis|
|Anti-hyperlipidemia drugs||Rosuvastatin calcium is an anti-hyperlipidemia drug which belongs to the inhibitor of HMG-CoA reductase successfully developed by the British AstraZeneca company. It is suitable for the treatment of various lipid abnormalities, including hypercholesterolemia, mixed lipid qualitative abnormalities and simple hypertriglyceridemia. Rosuvastatin calcium is listed as the strongest and the most comprehensive statins drugs which has entered into market for lipid-lowering and adjustment. Compared with atorvastatin which is currently recognized with the world's best efficacy, it has a better effect of lowering the level of LDL cholesterol and increasing the level of high-density lipoprotein. Moreover, it has a better tolerance, lower side effects and unique pharmacokinetic characteristics with the half-life about 20h. It only needs to be taken once a day.
|Pharmacological effects||Rosuvastatin is a selective inhibitor of HMG-CoA reductase. HMG-CoA reductase inhibitor is the rate-limiting enzyme of the transition hydroxy-3-methylglutaryl coenzyme A to valerate A (The precursor of cholesterol). The main site of action of rosuvastatin is liver - the target organs of cholesterol-lowering. Rosuvastatin increases the number of hepatic LDL receptors on the cell surface, promoting the absorption and catabolism of LDL, inhibits hepatic synthesis of VLDL, thereby reducing the total number of VLDL and LDL particles. |
For patients of homozygous and heterozygous familial hypercholesterolemia, non-familial hypercholesterolemia, and mixed dyslipidemia, Rosuvastatin can lower the total cholesterol, LDL-C levels, ApoB levels, non-HDL-C levels. Rosuvastatin also reduces the level of TG and increase the level of HDL-C. For patients of pure hypertriglyceridemia, rosuvastatin can lower total cholesterol, LDL-C, VLDL-C, ApoB, non-HDL-C, TG levels and increase the HDL-C levels.
Based on the general safety of pharmacology, repeated dose toxicity, potential genetic toxicity and the clinical information of carcinogenicity, no special toxicity was found for rosuvastatin on the human body. For studies on rat before and after birth, Rosuvastatin has obvious reproductive toxicity. It reduces the size, weight of the litter and birth rate. Treating female rats with a toxic dose which causes several times higher systemic exposure levels than the therapeutic exposure can enable the observation of these phenomena.
The above information is edited by the Chemicalbook of Dai Xiongfeng.
|Pharmacokinetics||The drug can be absorbed in great amount by liver after oral administration with the volume of distribution at 134 L. After 3 ~ 5 hours, plasma concentration reaches the peak. The absolute bioavailability is around 20%. Plasma protein binding rate (mainly albumin) is about 90%. About 90% of the total dose of rosuvastatin is excreted by feces as prototype (including the absorption of the active substance and unabsorbed), with the rest excreted through the urine. 5% rosuvastatin in urine is in the form of prototype. Half-life of plasma elimination is about 19 hours. Elimination half-life doesn’t increase with increased dose. The geometric mean of plasma clearance rate is about 50L/hour (coefficient of variation 21.7%). Same as other HMG-CoA reductase inhibitors, the uptake of rosuvastatin by liver involves the participation of membrane transporter OATP-C. The transporter is important in the liver for the clearance of rosuvastatin.
|Drug Interactions||1. Cyclosporine: when this product is used in combination with cyclosporine, the AUC of rosuvastatin is averagely 7 times higher than that observed in healthy volunteers (compared with the same dose using this service). Combination usage does not affect the plasma concentrations of cyclosporine. |
2. Vitamin K antagonists: same as other HMG-CoA reductase inhibitor, for patients of simultaneously usage of vitamin K antagonists (such as warfarin), at the beginning or gradually increasing the dose of this product may cause the increase of INR (international normalized ratio). Stop using the product or gradually decreasing the dose can lead to decrease in INR. In this case, appropriate INR testing is needed.
3. Combination of gemfibrozil, fenofibrate, other fibrates and lipid-lowering doses (≥1g / day) of niacin with HMG-CoA reductase inhibitors can increase the risk of myopathy, which may be due to that they can cause myopathy when given alone.
4. Antacids: Mixing the product and one antacid containing aluminum hydroxide and magnesium for suspension can reduce the concentration of statin rosuvastatin plasma by 50%. Taking antacids two hours after taking this can further reduce the impact. The clinical significance of this drug interaction has not been studied.
5. Erythromycin: Combination with erythromycin can cause rosuvastatin AUC (0 ~ t) decrease by 20% and Cmax decrease by 30%. This interaction may be due to the gastrointestinal motility caused by increase of erythromycin.
6. Oral administration of contraceptives / hormone replacement therapy (HRT): while using this drug together with oral contraceptives can cause the increase of ethinyl estradiol and norgestrel AUC by 26% and 34%, respectively. When choosing the dose of oral contraceptives, the patients should consider the increase of the plasma concentration of these drugs. Yet there are no pharmacokinetic data on taking rosuvastatin and HRT together. Therefore, we cannot exclude the presence of similar interactions. However, in clinical trials, this kind of combination is widely applied and can be well tolerated by patients.
Figure 1 Synthesis pathways of Rosuvastatin calcium
|Indications||Primary Hypercholesterolemia: Usual dose of rosuvastatin calcium (10 mg) can significantly reduce LDLC levels in patients of primary hypercholesterolemia, and has a better efficacy compared with atorvastatin calcium (10mg). At the end of the experiment, TC, TG levels drop even more. Moreover, 5 mg of rosuvastatin calcium within the same eight weeks of treatment has a better effect on reducing LDLC level compared with 10 mg atorvastatin calcium. The difference is statistically significant, suggesting that the lipid-lowering effect of rosuvastatin calcium is better than that of atorvastatin calcium. Our experimental results are also consistent with the other previous assessment (STELLAR, MERCURY) about efficacy studies on statin drugs. Rosuvastatin calcium has a stronger LDLC-lowering effect than the other statins drugs (atorvastatin, simvastatin and pravastatin), allowing more patients to achieve recommended treatment goals.|
Elderly coronary heart disease combined hyperlipidemia: Rosuvastatin calcium is capable of competitively inhibiting liver methylglutaryl coenzyme A reductase, and further exerts its good effect on reducing the fat. It has a long half-life. The gender and age of patients have no significant effect on the metabolism of drugs. The drug has only a few of adverse reactions. Meanwhile, the drug can also effectively promote the transport of low-density lipoprotein into cells, thus improving the cleaning effect of LDL, and playing a role in effectively lowering LDL. In addition, rosuvastatin calcium may also inhibit the aggregation of platelet, reduce the body's inflammatory response and protect their endothelial cells, effectively stabilize the plaque of patients suffering coronary artery disease to reduce its impact on the patient. The patients of experimental group in our hospital were treated with rosuvastatin calcium, which gives a significantly better lipid-lowering effect than patients in the control group, P <0.05, the difference was statistically significant. This further illustrates the usage of rosuvastatin calcium for treatment of elderly coronary heart disease combined hyperlipidemia has a good effect which can improve efficacy, reduce the blood fat with high clinical significance.
|Safety||In terms of safety issue, the incidence of adverse cases for rosuvastatin calcium was similar to that of other related drugs. Adverse cases include elevated ALT, increased GGT and nausea.
|Side effects||1. Adverse reactions of this product are generally mild and transient such as common headache, dizziness, constipation, nausea, abdominal pain, muscle pain and weakness. |
2. For observed patients, the increase of creatine kinase (CK) levels is dose-related; the majority of cases were mild, asymptomatic and transient. Stop the treatment once the CK levels elevate (> 5 × ULN).
3. Impact on the liver: for a small number of patients, it was observed for a drug dose-related increase in transaminases; the majority of cases were mild, asymptomatic and transient.
|Uses||For making lipid-lowering drugs.
|Chemical Properties||White to Off-White Crystalline Solid|
|Usage||A selective, competitive HMG-CoA reductase inhibitor. Antilipemic.|
|Rosuvastatin calcium Preparation Products And Raw materials|