Abstract
In order to find a new type of hypolipidemic drug, we carried out screening of an inhibitor of cholesterol synthesis from microorganisms and found ML-236B, as a potent and specific inhibitor of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase, the ratelimiting enzyme in the pathway of cholesterol biosynthesis. Among many derivatives of ML-236B, pravastatin sodium (pravastatin) was finally selected because of its potency and tissue selectivity.
Pravastatin strongly inhibited sterol synthesis in rat hepatocytes, but only weakly inhibited that in cells from nonhepatic tissues. The selective inhibitory activity of pravastatin in sterol synthesis was further confirmed by ex vivo and in vivo experiments using rats and mice. This characteristic of pravastatin is based on its hydrophilic nature a hydrophilic compound hardly permeates plasma membrane, whereas a hydrophobic (lipophilic) one easily permeates it. In hepatocytes, on the other hand, pravastatin is actively incorporated via organic anion transporter.
Pravastatin demonstrated a preventive effect on the development of coronary atherosclerosis and xanthomatosis in young Watanabe heritable hyperlipidemic (WHHL)rabbits, as a consequence of keeping their serum cholesterol levels low. In clinical study, pravastatin preferentially reduced low-density lipoprotein cholesterol by 27% at 10-20mg/day with low side effects.
