title: Inhibition of cholesterol synthesis and hepatic 3-hydroxy-3-methylglutaryl--CoA reductase in rats by simvastatin and pravastatin.
abstract: In this communication we attempt to provide one possible explanation for the observed differences regarding kinetics and distribution between simvastatin and pravastatin. Rats treated with simvastatin or pravastatin exhibited a reduction in the incorporation of [2-(14)C] acetate into liver cholesterol and displayed lower plasma mevalonate levels as compared to control animals. Moreover, both the total and dephosphorylated 3-hydroxy-3-methylglutaryl--CoA (HMG-CoA) reductase (EC 1.1.1.34) activities, particularly 1 h after treatment, were greatly reduced in liver microsomes obtained from simvastatin-treated as compared to control rats. During the same time frame, these parameters were actually elevated 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, was no longer bound to the enzyme; however, it had entered the liver because its inhibitory effect on cholesterol synthesis was manifest at early times after administration. These data provide a plausible rationale for the earlier observation that activity of simvastatin persists longer in plasma than does that of pravastatin.
authors.affiliation: Department of Medical Chemistry and Biochemistry, University of Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Del Puppo
authors.forename: S
authors.initials: S
authors.lastname: Rauli
authors.forename: M
authors.initials: M
authors.lastname: Galli Kienle
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D002784:Cholesterol / Q000096:biosynthesis*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D008798:Mevalonic Acid / Q000097:blood; D008862:Microsomes, Liver / Q000201:enzymology; D017035:Pravastatin / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin
chemical_list: D000924:Anticholesteremic Agents; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D002784:Cholesterol; D008148:Lovastatin; D019821:Simvastatin; D017035:Pravastatin; D008798:Mevalonic Acid