THE MECHANISM OF LACK OF HYPOCHOLESTEROLEMIC EFFECTS OF PRAVASTATIN SODIUM, A 3-HYDROXY-3-METHYLGLUTARYL COENZYME-A REDUCTASE INHIBITOR, INRATS

In order to clarify the reason why pravastatin, a 3-hydroxy-3-methylgl utaryl (HMG)-CoA reductase inhibitor, did not show hypocholesterolemic effects in rats, the changes of various parameters affecting the seru m cholesterol levels by pravastatin were determined in rats and rabbit s, as a comparison. In rabbits, pravastatin administration at 50 mg/kg for 14 days decreased serum and liver cholesterol by 40% and 8%, resp ectively. The hepatic LDL receptor activity was increased 1.7-fold, an d VLDL cholesterol secretion was decreased. Cholesterol 7 alpha-hydrox ylase activity was not changed. In contrast, in rats, serum cholestero l was increased by 14% at 50 mg/kg and 27% at 250 mg/kg for 7 days, re spectively. At 250 mg/kg, liver cholesterol was significantly increase d by 11%. Under these conditions, neither the hepatic LDL receptor act ivity nor cholesterol 7 alpha-hydroxylase was changed, and VLDL choles terol secretion was increased. At 250 mg/kg, net cholesterol synthesis in rat liver was increased after 7 days of consecutive administration . These results imply that in rats, stimulated net cholesterol synthes is caused the increase of liver cholesterol followed by the increase o f VLDL cholesterol secretion, and resulted in the raise of plasma chol esterol. Although hepatic HMG-CoA reductase was induced almost the sam e fold in both animals at 50 mg/kg, the induced HMG-CoA reductase acti vity in rats might overcome the inhibitory capability of pravastatin, resulting in an increase of net cholesterol synthesis, but not in rabb its. This overresponse to pravastatin in rats might cause the lack of hypocholesterolemic effects of this drug.