Inhibition of cholesterol synthesis ex vivo and in vivo by fluvastatin, a new inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase.
The inhibitory effect of fluvastatin sodium (fluvastatin), a new type of 3-hydroxy-3-methylglutaryl (HMG) coenzyme A inhibitor, on de novo cholesterol synthesis was investigated and compared with that of pravastatin. Fluvastatin at a concentration of 12.5 mg/kg inhibited sterol synthesis ex vivo from [14C]acetate in rat liver and ileum by 97-99% with respect to the control, while the inhibition in kidney was 55%. The inhibition by fluvastatin in the liver and ileum persisted for approximately 9 h after administration. Significant differences between fluvastatin also had an inhibitory effect on cholesterol synthesis in vivo in various tissues of rats given [14C]acetate intraperitoneally. Sterol synthesis in the liver, ileum and kidney was inhibited by over 95% 3 h after administration of 6.25 mg/kg of fluvastatin. Significant differences between fluvastatin and pravastatin were found in the liver and ileum. Fluvastatin was more potent than pravastatin in inhibiting both ex vivo and in vivo sterol synthesis in the ileum (but not in kidney) and liver.
Yamamoto
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A
Department of Pharmacology, Hokkaido Institute of Pharmaceutical Sciences, Otaru, Japan.
Itoh
S
S
Hoshi
K
K
Ichihara
K
K
D000085:Acetates / Q000378:metabolism; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D002250:Carbon Radioisotopes; D002784:Cholesterol / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D000077340:Fluvastatin; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009928:Organ Specificity; D017035:Pravastatin / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013261:Sterols / Q000096:biosynthesis
D000085:Acetates; D000924:Anticholesteremic Agents; D002250:Carbon Radioisotopes; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D013261:Sterols; D000077340:Fluvastatin; D002784:Cholesterol; D017035:Pravastatin