抄録
Pravastatin sodium (hereafter referred as pravastatin), lovastatin and simvastatin are known as the strong inhibitors of HMG-CoA reductase, the rate limiting enzyme of cholesterol biosynthesis. They are now under clinical trials or already on a market. The first potent inhibitor of the enzyme was ML-236B (compactin), the mother compound of pravastatin. Among the many derivatives of ML-236B including microbial and chemically synthesized ones, pravastatin was selected by its potency and tissue-selective inhibition.
Pravastatin selectively inhibited the sterol synthesis in liver and intestine, the major sites of cholesterogenesis, but only weakly inhibited in other organs including hormone producing ones. In contrast to pravastatin, lovastatin inhibited the sterol synthesis not only in liver and intestine but also in other organs. The findings were supported by the experiments using various kinds of isolated and cultured cells. These different features in tissue selectivity could be ascribed the difference in cellular uptake of these drugs.Pravastatin showed a hypolipidemic activity in dogs, monkeys, rabbits and WHHL rabbits, an animal model for familial hypercholesterolemia (FH) in man. Moreover, pravastatin demonstrated a preventive activity on the progression of coronary atherosclerosis and xanthoma in immature WHHL rabbit. In clinical trials, pravastatin exhibited a potent hypolipidemic activity at a low dose, 5mg b. i. d., even in FH patients. In the long-term trial (15 month), LDL cholesterol was reduced by 27.2%, while HDL cholesterol was inversely increased by 9.2%. No serious side effect and abnormal laboratory finding was reported in these trials.
HMG-CoA reductase inhibitors including pravastatin, lovastatin and simvastatin are the most potent cholesterol lowering drugs among currently available, with less side effects. In particular, pravastatin is expected to have a preventive effect on the progression of atherosclerosis and xanthoma in hypercholesterolemic subjects.
