REVIEW PAPER INTERNATIONAL JOURNAL OF PHARMACY AND PHARMACEUTICAL ANALYSIS (2017, VOl. 01(02) WWW.IJPPA.COM ISSN: 2394-1618 Page numbers:96-105 ISSN:XXXXX “A REVIEW ON ROSUVASTATIN” AISWARYA S*, GOWRISANKAR N L, FARSENA A AND SREE LAKSHMI P S *Department of Pharmaceutics, Prime College of Pharmacy, Erattayal, Palakkad-678551, Kerala, India ABSTRACT Rosuvastatin is a new generation HMG-CoA reductase inhibitor which exhibits some unique pharmacologic and pharmacokinetic properties. It has low extra hepatic tissue penetration, low potential for CYP3A4 interactions and substantial LDL-C lowering capacity and therefore has distinct advantages. Present review provides an account of pharmacology of rosuvastatin, highlighting its efficacy and safety and a brief comparison with other statins. Keywords: Rosuvastatin, Cardiovascular risk, Statins, Low density lipoprotein cholesterol. *Address of the corresponding author: Aiswarya S, M.Pharm, Department of Pharmaceutics, Prime college of Pharmacy, Erattayal, Mobile: 8547053123, E-mail address: [email protected] INTRODUCTION and the incidence of cardiovascular Cholesterol is a waxy, fat like substance disease. The associated morbidity and that is found in all cells of the body. Our mortality is positively correlated to low body needs some cholesterol to make density lipoprotein cholesterol (LDL) and hormones, vitamin D, and substances that inversely related to high density help you process nourishment. Our body lipoprotein cholesterol (HDL). [1, 2] makes all the cholesterols it needs. Ischemic heart diseases are the leading Cholesterols go through our circulatory cause of mortality worldwide and system in little bundles called lipoprotein. constitute a major health burden. These bundles are made of fat within and According to world health organization proteins on the outside. Two sorts of statistics it accounts for 12.8% of death, lipoproteins convey cholesterol all with strokes and other cerebrovascular through your body. Low thickness disease accounting for 10.8 %. In United lipoproteins (LDL) and high thickness Kingdom, data from the Health survey for lipoproteins (HDL). Having sound levels England suggest that while mortality may of both sorts of lipoproteins is important. decline, cardiovascular disease morbidity Epidemiological studies have established continues to rise. Epidemiology studies a strong correlation between cholesterol have established a strong correlation REVIEW PAPER INTERNATIONAL JOURNAL OF PHARMACY AND PHARMACEUTICAL ANALYSIS (2017, VOl. 01(02) WWW.IJPPA.COM ISSN: 2394-1618 Page numbers:96-105 ISSN:XXXXX between cholesterol and the incidence of ischemic heart disease patients, cardiovascular disease. The associated irrespective of the cholesterol morbidity and mortality is positively concentration. In addition to the correlated to low density lipoprotein beneficial cholesterol lowering effects, cholesterol and inversely related to high statins improve endothelial function, density lipoprotein cholesterol.[3, 4] enhance stability of atherosclerotic Statins are 3-hydroxy-3-methylglutaryl plaques, and inhibit inflammatory as well coenzyme A (HMG Co A) reductase as thrombogenic responses in arterial inhibitors that are effective in the walls. Furthermore extensive post reduction of total and LDL cholesterol. [5] marketing surveillance has shown that A number of large randomized control long term statin therapy is generally well trials have demonstrated unequivocally tolerated. [11] that lowering LDL-C particularly with The reduction in cardiovascular events statins reduces the risk of cardiovascular from statins therapy is proportional to deaths and events. [6] HMG CoA inhibitors the LDL-C reduction; larger reductions in have been shown to prevent initial LDL-C are associated with greater cardiovascular events and subsequent reduction in cardiovascular events, so cardiovascular events in ischemic heart more potent statins results in greater disease patients, irrespective of the cardiovascular risk reduction. [12] cholesterol concentration. [7,8] In addition In this review, we outline the to the beneficial cholesterol lowering pharmacology of rosuvastatin, highlights effects, statins improve endothelial its effects on cholesterol level, sides function, enhance stability of effects and contraindications. atherosclerotic plaques, and inhibit inflammatory as well as thrombogenic DRUG CLASS AND MECHANISM responses in arterial walls. [9] Rosuvastatin is an oral drug for lowering Furthermore extensive post marketing blood cholesterol levels. surveillance has shown that long term It belongs to a class of drug called HMG- statin therapy is generally well tolerated. CoA reductase inhibitors, more commonly [10] referred to as statins. Other drugs in this The reduction in cardiovascular events class include; from unequivocally that lowering LDL-C *Simvastatin (Zocor) particularly with statins reduces the risk *Lovastatin (Mevacor) of cardiovascular deaths and events. *Pravastatin (Pravachol) HMG CoA inhibitors have been shown to *Atrovastatin (Lipitor) prevent initial cardiovascular events and *Fluvastatin (Lescol) subsequent cardiovascular events in REVIEW PAPER INTERNATIONAL JOURNAL OF PHARMACY AND PHARMACEUTICAL ANALYSIS (2017, VOl. 01(02) WWW.IJPPA.COM ISSN: 2394-1618 Page numbers:96-105 ISSN:XXXXX These drugs reduce cholesterol levels by PHARMACOKINETICS inhibiting HMG-CoA reductase, an enzyme The oral bioavailability of rosuvastatin is that produces cholesterol in the lever. 20 %, which is comparable to Rosuvastatin and other statins lower atorvastatin, pravastatin and fluvastatin, blood total cholesterol as well as blood and qualitatively higher than simvastatin LDL cholesterol levels. LDL cholesterol is and lovastatin. After a single oral dose the the bad type of cholesterol that increases peak plasma concentration is reached at 5 the risk of coronary artery disease and hours. This is longer than other HMG-CoA heart attacks. Lowering LDL cholesterol inhibitors which achieve maximum levels shows the progression of coronary plasma concentrations in less than 3 artery disease and may even reverse it. hours. In compiled data from Statins also increase HDL cholesterol, the pharmacokinetic trials, the peak plasma good type of cholesterols, and reduce concentration and area under the triglycerides. concentration time curve show a largely linear relationship as the dose of PHARMACOLOGY rosuvastatin increases from 5 to 80 mg. Rosuvastatin is a fully synthetic HMG-CoA Food intake decreases the rate of reductase inhibitor. Other HMG-CoA absorption of rosuvastatin by 20 % but reductase inhibitors are either natural, not the extent of absorption. This does mevinic acid derived (lovastatin, not reduce the cholesterol lowering simvastatin, pravastatin ) or synthetic, potency; therefore rosuvastatin can be heptenoic acid derived (atorvastatin, taken with or without food, and in the fluvastatin). Rosuvastatin belongs to a morning or evening. [13-18] new generation of methane • Approximately 90 % of rosuvastatin is sulphonamide •pyrimidine and N- protein bound mainly to albumin; other methane sulfonyl pyrrole-substituted 3, statins have approximately 95 % protein 5-dihydroxy-heptenoates. Although the binding except pravastatin which has a characteristic statin pharmacophore lower protein binding of 50 %. The mean remains similar to other statins, the volume of distribution is 134 litres in addition of a stable polar methane- steady state. Rosuvastatin is less sulphonamide group provides low lipophilic than other statins such as lipophilicity and enhanced ionic atorvastatin and simvastatin but more interaction with HMG-CoA reductase lipophilic than pravastatin. Penetration of enzyme thus improving its binding statins into extra-hepatic tissues occurs affinity to this enzyme. by passive diffusion and is dependent on their lipophilicity. This has implications on their muscle safety as increased REVIEW PAPER INTERNATIONAL JOURNAL OF PHARMACY AND PHARMACEUTICAL ANALYSIS (2017, VOl. 01(02) WWW.IJPPA.COM ISSN: 2394-1618 Page numbers:96-105 ISSN:XXXXX rhabdomyolysis was reported in patients rosuvastatin is responsible for on lipophilic agents like cerivastatin and approximately 90 % of plasma HMG-CoA lovastatin. [19, 20] inhibitor activity. Rosuvastatin is less Human hepatocyte studies indicate that likely to cause metabolic drug to drug rosuvastatin is a poor substrate for interactions since it has limited metabolism by cytochrome P450 and metabolism by CYP isoenzymes. Other hence 90 % of the drug is excreted HMG-CoA reductase inhibitors such as unchanged. CYP2C9 is the main atorvastatin and simvastatin are isoenzyme involved in metabolism with metabolised via CYP3A4. Their plasma minimal effect from CYP2C19. concentrations are increased by Rosuvastatin is metabolised to an N- inhibitors of CYP3A4 such as itraconazole, desmethyl metabolite which is less potent protease inhibitors and macrolide than the parent drug in inhibiting HMG- antibiotics. CoA reductase activity. The parent drug Table 1. Compares the pharmacokinetics of different statins Parameter Rosuva Atorva Simva Prava Fluva Pitava Lova statin statin statin statin statin statin statin Tmax (h) 3 2–3 1.3–2.4 0.9–1.6 0.4–2.1 0.6–0.8 2–4 Bioavailability 20 12 5 18 24 80 5 Lipophilicity No Yes Yes No Yes Yes Yes Protein 88 80–90 94–98 43–55 .98 96 95 binding Minimal Sulfation CYP2C9 Minimal Biliary Metabolism CYP2C19 CYP3A4 CYP3A4 CYP2C9 CYP2C8 CYP3A4 & urine Biliary CYP2C9 excretion excretion Active Active Metabolites Active Active