Tissue-selective inhibition of sterol synthesis in mice by pravastatin sodium after a single or repeated oral administrations.

Abstract

Pravastatin, an inhibitor of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase, exhibits liver-selectivity in inhibiting sterol synthesis, when administered as a single oral dose to mice or rats, whereas lovastatin and simvastatin do not. This may be due to the fact that pravastatin is distributed intracellularly, to a large extent, in the liver and extracellularly in nonhepatic tissues. In the present study, we examined whether the difference in liver-selectivity among these three HMG-CoA reductase inhibitors observed in single-dose studies was preserved after repeated oral administrations of drugs to mice. De novo sterol synthesis in different tissues of mice was examined in vivo three hours after the last dose of drug by measuring incorporation of intraperitoneally injected [14C]acetate into total sterols. Pravastatin administered orally for 11 consecutive days at 5 and 10 mg/kg exhibited a greater liver-selectivity than lovastatin and simvastatin: sterol synthesis was inhibited more than 60% in the liver by all three drugs, whereas that in nonhepatic tissues was inhibited less than 10% by pravastatin and more than 30% by lovastatin and simvastatinin in most of the nonhepatic tissues examined. Pravastatin administered orally for 11 consecutive days at 10 mg/kg caused more selective inhibition of sterol synthesis in liver ex vivo than two other inhibitors at the same dose. Pravastatin inhibited de novo sterol synthesis from [14C]acetate into sterol fraction in the liver slices in vitro, but minimally in those of the spleen and testis, whereas lovastatin and simvastatin inhibited in those of all three tissues.(ABSTRACT TRUNCATED AT 250 WORDS)