Rosuvastatin, a new HMG-CoA Reeductase Inhibitor with advantages over other available statins

The Food and Drug administration (FDA) approved a new HMG-CoA reductase inhibitor (rosuvastatin) on august, 2003. Rosuvastatin, is a synthetic, single enantiomer formulated and administered as the calcium salt. Although, dihydroxy heptenoic acid side chain is characteristic of the statin class, but one particular feature of the rosuvastatin molecule is a polar methane sulphonamide group that confers a relatively low lipophilicity, which make rosuvastatin relatively hydrophilic^1,2 and hepatoselective^1,2,3.

Mechanism of action: rosuvastatin is a reversible competitive inhibitor of HMG-CoA reductase, which is the most important rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor for cholesterol^1,4. In overall, few studies strongly suggest that rosuvastatin has the relatively greater binding to HMG-CoA reductase in comparison to other statins^5,6. Rosuvastatin is relatively selective for liver and as a result of this action it increases the number of hepatic LDL receptors, which has been shown to increase ten time more by this drug in comparison to pravastatin². This increase in LDL receptors enhances the uptake and catabolism of Low Density Lipoprotein (LDL) and Very Low-Density Lipoprotein (VLDL). This ultimately results in reduced concentrations of VLDL and LDL in the circulation^2,4,7. Additionally, significant increase in High Density Lipoprotein (HDL) is also observed with the use of rosuvastatin⁸. It is more potent than other statins such as atorvastatin, simvastatin and is 8-fold more potent than the hydrophilic comparator, pravastatin^5,6.

Pharmacokinetic advantages: the absorption of rosuvastatin  in man was moderately rapid with peak plasma levels (t_max) occurring within 3-5 hours of oral administration. 18-20 hours has been suggested to be the terminal (t½) of rosuvastatin which is relatively long compared with other statins⁹. Co-administration of rosuvastatin with food although reduce the rate but not the extent and LDL lowering effect of the drug¹⁰. One of the study showed that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes¹¹. Which suggest there may be low propensity for drug interactions mediated by cytochrome P450^12,13. Moreover, rosuvastatin undergoes limited metabolism and approximately 90% of the drug is excreted unchanged in the faeces¹¹.

Clinical supremacy over other statins: recent clinical studies suggest rosuvastatin to be more effective than existing statins^8,14-19. Most recent clinical trials comparing the lipid modifying efficacy of statins showed greater efficacy of rosuvastatin in reducing LDL cholesterol compared with atorvastatin, simvastatin and pravastatin⁸. Also the greater LDL cholesterol reduction was achieved across the dose ranges (10-80mg) with rosuvastatin than with other statins. HDL Cholesterol was increased significantly better with rosuvastatin when it was compared across the doses ranges with statins in many recent studies^8,18. Rosuvastatin also produce significantly better reduction in total cholesterol^8,17 and similar or significantly better reductions of serum triglycerides⁸ levels and favorable lipid ratio^18,19 in comparison to atorvastain, simvastatin and pravastatin. It is also suggested that the greater LDL cholesterol reduction with rosuvastatin then with the comparators resulted in higher percentage of patients who achieved National Cholesterol Education Program (NCEP) and European LDL Cholesterol goals^8,17. Rosuvastatin is available in 5,10,20 & 40mg tablets but most importantly, rosuvastatin can achieve most of this lipid modifying benefits at a dose of 10mg/per day⁸. In one of the trial in special population groups i.e. age > 65, female sex, post-menopausal status, hypertension, atheroscelorsis, type-2 diabetes and obesity,  suggested that rosuvastatin had consistent efficacy across these sub-groups¹⁶. Similarly one investigation  suggested greater reduction of coronary artery disease risk because of the fact rosuvastatin achieves better lipid lowering goals in comparison to other statins¹⁷. In metabolic syndrome²⁰ and in patients with typeIIa or IIb hypercholesterolemia¹⁸ their supremacy over other available statins  also have been suggested.

Non-lipid (Pleitropic effects) of rosuvastatin: rosuvastatin has been shown to exert anti-inflammatory²¹ effects on the microvascular endothelial independent of its lipid lowering actions as well as to induce nitric oxide²² significantly from the vasculature and attenuate post ischemic myocardial injury following ischemia and reperfusion in mice. Thereby, indicating direct vascular and cardioprotective effects of rosuvastatin independent of its lipid lowering actions²².

Rosuvastatin is well tolerated with most commonly adverse effects being headache, dizziness, constipation, nausea, abdominal pain, myalgia and asthenia²³. Active liver disease, severe renal impairment and myopathy are some of its contraindications²⁴. Presently, rosuvastatin is indicated in patients with primary hypercholesterolemia (heterozygous familial and non-familial), mixed dyslipidemia (type-IIa and IIb) and with elevated serum TG levels (Fredricken type IV) patients.

In conclusion: rosuvastatin differ from other statins and offer many important advantages over the currently available statins in the form of low lipophilicity, high hepatocyte selectivity, minimal metabolism, low propensity for cytochrome P450 drug interactions and high potency. Moreover, rosuvastatin is significantly more effective at reducing LDL-cholesterol and get significantly more patient to their European  and U.S NCEP ATP III, LDL-cholesterol goals. Additionally, non-lipid cardioprotective effects provided by rosuvastatin suggest that this newly introduced statin might become the drug of first choice for many patients with dyslipidemia in future.

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REFERENCES:

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About Authors

Dr Vishal R.Tandon has received his doctorate in Pharmacology
from Nagpur University, Maharashtra (India) in Dec, 2002.He has authored and/or
coauthored over 55 publications in many national and international journals. Two
chapters in different national books are also to his credit. His research interests
include herbal drug screening, especially working on plant Vitex negundo. He is
Expertise in designing and conducting clinical trials. He is currently working
as Senior Demonstrator Post graduate department of pharmacology and therapeutics,
GMC, Jammu (J&K)-India. His current job responsibilities include teaching
UG/PG classes as well as supervising research. He bears following post, a) Editorial
Secretary JK-SCIENCE, Journal of Medical
Education & Research . This Journal is indexed in Excerpta Medica/EMBASE,
Ulrich periodical Dictionary& Indian Science Abstract. b) Secretary-Indian
Rheumatology Association-J&K CHAPTER. c) Pear reviewer World Journal of Medical
Science. He is also life Member of Indian Pharmacological society, Association
of Physiologist and Pharmacologist of India, Indian Rheumatology Association and
Indian Menopause Society.

Co Author-

Dr. B. M. Gupta is working presently as (Lecturer)

Post Graduate Department of Pharmacology & Therapeutics

GMC, Jammu (J&K) India - 180001.