Tissue selectivity of pravastatin sodium, lovastatin and simvastatin. The relationship between inhibition of de novo sterol synthesis and active drug concentrations in the liver, spleen and testis in rat.
Tissue selectivity of pravastatin sodium (pravastatin), lovastatin and simvastatin, 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors was examined by measuring inhibition of de novo sterol synthesis and active drug concentrations in the liver, spleen and testis in rats after a single oral administration (25 mg/kg) of these drugs. Regarding tissue drug concentrations, all three drugs were liver selective: concentrations of drugs in the liver were about ten-times higher than those in the spleen and testis. On the other hand, pravastatin was far more liver selective in inhibiting sterol synthesis than two other inhibitors: pravastatin inhibited de novo sterol synthesis in the liver but minimally in the spleen and testis, whereas lovastatin and simvastatin inhibited in all three tissues. Microautoradiographic and in vitro cellular-uptake studies demonstrated that pravastatin remained in the extracellular space in the spleen, whereas the other drugs entered the cell. We conclude that pravastatin exhibits a liver-selective inhibition of sterol synthesis because the agent permeates the cell membrane in the liver, but not in non-hepatic tissues.
Koga
T
T
Biological Research Laboratories, Sankyo Co., Ltd, Tokyo, Japan.
Fukuda
K
K
Shimada
Y
Y
Fukami
M
M
Koike
H
H
Tsujita
Y
Y
D000818:Animals; D001345:Autoradiography; D002250:Carbon Radioisotopes; D004305:Dose-Response Relationship, Drug; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008148:Lovastatin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D009928:Organ Specificity; D017035:Pravastatin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D019821:Simvastatin; D013154:Spleen / Q000187:drug effects / Q000378:metabolism*; D013261:Sterols / Q000096:biosynthesis*; D013737:Testis / Q000187:drug effects / Q000378:metabolism*; D014018:Tissue Distribution
D002250:Carbon Radioisotopes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D013261:Sterols; D008148:Lovastatin; D019821:Simvastatin; D017035:Pravastatin