title: 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.
abstract: 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.
authors.affiliation: Biological Research Laboratories, Sankyo Co., Ltd, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Koga
authors.forename: K
authors.initials: K
authors.lastname: Fukuda
authors.forename: Y
authors.initials: Y
authors.lastname: Shimada
authors.forename: M
authors.initials: M
authors.lastname: Fukami
authors.forename: H
authors.initials: H
authors.lastname: Koike
authors.forename: Y
authors.initials: Y
authors.lastname: Tsujita
mesh_terms: 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
chemical_list: D002250:Carbon Radioisotopes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D013261:Sterols; D008148:Lovastatin; D019821:Simvastatin; D017035:Pravastatin