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Preclinical and clinical pharmacology of rosuvastatin, a new 3-hydroxy- 3-methylglutaryl coenzyme A reductase inhibitor1

      Abstract

      Rosuvastatin (formerly known as ZD4522) is a new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin) with distinct pharmacologic properties. Compared with most other statins, it is relatively hydrophilic, similar in this respect to pravastatin. Rosuvastatin has been shown to be a comparatively potent inhibitor of HMG-CoA reductase activity in a purified preparation of the catalytic domain of the human enzyme, as well as in rat and human hepatic microsomes. In rat hepatocytes, rosuvastatin was found to have significantly higher potency as an inhibitor of cholesterol synthesis than 5 other statins. Rosuvastatin was approximately 1,000-fold more potent in rat hepatocytes than in rat fibroblasts. Further studies in rat hepatocytes demonstrated that rosuvastatin is taken up into these cells by a high-affinity active uptake process. Rosuvastatin was also taken up selectively into the liver after intravenous administration in rats. Potent and prolonged HMG-CoA reductase inhibitory activity has been demonstrated after oral administration to rats and dogs. Pharmacokinetic studies in humans using oral doses of 5 to 80 mg showed that maximum plasma concentrations and areas under the concentration-time curve are approximately linear with dose. The terminal half-life is approximately 20 hours. Studies with human hepatic microsomes and human hepatocytes have suggested little or no metabolism via the cytochrome P-450 3A4 isoenzyme. On the basis of these observations, it is suggested that rosuvastatin has the potential to exert a profound effect on atherogenic lipoproteins.
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