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

Rosuvastatin (formerly ZD4522) is a new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin) with distinct pharmacologic prope rties. Compared with most other statins, it is relatively hydrophilic, simi lar in this respect to pravastatin. Rosuvastatin has been shown to be a com paratively potent inhibitor of HMG-CoA reductase activity in a purified pre paration of the catalytic domain of the human enzyme, as well as in rat and human hepatic microsomes. In rot hepatocytes, rosuvastatin was found to ha ve significantly higher patency as an inhibitor of cholesterol synthesis th an 5 other statins. Rosuvastatin was approximately 1,000-fold more potent i n rat hepatocytes than in rat fibroblasts. Further studies in rat hepatocyt es demonstrated that rosuvastatin is taken vp into these cells by a high-af finity active uptake process. Rosuvastatin was also token up selectively in to the liver after intravenous administration in rats. Potent and prolonged HMG-CoA reductase inhibitory activity has been demonstrated after oral adm inistration to rats and dogs. Pharmacokinetic studies in humans using oral doses of 5 to 80 mg showed that maximum plasma concentrations and areas und er the concentration-time curve are approximately linear with dose. The ter minal half-life is approximately 20 hours. Studies with human hepatic micro somes and human hepatocytes have suggested little or no metabolism via the cytochrome P-450 3A4 isoenzyme. On the basis of these observations, it is s uggested that rosuvastatin has the potential to exert a profound effect on atherogenic lipoproteins. (C) 2001 by Excerpta Medica, Inc.