INHIBITION OF CHOLESTEROL-SYNTHESIS AND HEPATIC 3-HYDROXY-3-METHYLGLUTARYL-COA REDUCTASE IN RATS BY SIMVASTATIN AND PRAVASTATIN

In this communication we attempt to provide one possible explanation f or the observed differences regarding kinetics and distribution betwee n simvastatin and pravastatin. Rats treated with simvastatin or pravas tatin exhibited a reduction in the incorporation of [2-C-14]acetate in to liver cholesterol and displayed lower plasma mevalonate levels as c ompared to control animals. Moreover, both the total and dephosphoryla ted 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase (EC 1.1.1.34) a ctivities, particularly 1 h after treatment, were greatly reduced in l iver microsomes obtained from simvastatin-treated as compared to contr ol rats. During the same time frame, these parameters were actually el evated with pravastatin treatment. It is known that HMG-CoA reductase synthesis and activity increase following their competitive inhibition . Our results suggest that pravastatin, at 1 h following treatment, wa s no longer bound to the enzyme; however, it had entered the liver bec ause its inhibitory effect on cholesterol synthesis was manifest at ea rly times after administration. These data provide a plausible rationa le for the earlier observation that activity of simvastatin persists l onger in plasma than does that of pravastatin.