Effect of crilvastatin, a new cholesterol lowering agent, on unesterified LDL‐cholesterol metabolism into bile salts by rat isolated hepatocytes

• Published in: British journal of pharmacology 1995-02, Vol.114 (3), p.624-631
• Main Authors: Clerc, Thierry, Sbarra, Véronique, Diaconescu, Nicolas, Lafont, Huguette, Jadot, Guy, Laruelle, Claude, Chanusso, Françoise
• Format: Article
• Language: English
• Subjects: Animals; Anticholesteremic Agents - blood; Anticholesteremic Agents - pharmacology; Anticholesteremic Agents - therapeutic use; Bile Acids and Salts - metabolism; bile salts; Binding Sites; Biological and medical sciences; Cells, Cultured; cholesterol; Cholesterol, LDL - blood; Cholesterol, LDL - metabolism; crilvastatin; Culture Media; Disease Models, Animal; Emulsions; General and cellular metabolism. Vitamins; hypercholesterolaemia; Hypercholesterolemia - drug therapy; Hypercholesterolemia - metabolism; Isolated hepatocytes; lipoproteins; Liver - cytology; Liver - drug effects; Liver - metabolism; Male; Medical sciences; Micelles; Pharmacology. Drug treatments; Proline - analogs & derivatives; Proline - blood; Proline - pharmacology; Proline - therapeutic use; Rats; Rats, Wistar
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.1995.tb17185.x

1 The aim of these experiments was to determine the effect of crilvastatin, a new cholesterol lowering agent, on the metabolism of unesterified low density lipoprotein (LDL)‐cholesterol by rat freshly isolated hepatocytes. This preclinical model was developed as an alternative to in vivo experiments, to mimic the metabolic effects of a molecule on its target cells and to define optimal conditions for future experimentation on human hepatocytes. 2 Cells were obtained from normolipidaemic or hypercholesterolaemic rats, hypercholesterolaemia was nutritionally induced. Incubations were performed in a medium containing 600 μm taurocholate and 50 μm or 300 μm crilvastatin. 3 This molecule was shown in vitro to be carried by physiological transporters, i.e., albumin‐bile salt micellar associations and LDL. Crilvastatin induced a significance increase in the synthesis and secretion by hepatocytes of bile salts resulting from the metabolism of unesterified LDL‐cholesterol in both normolipidaemic and hypercholesterolaemic rats. Stimulation involved non‐conjugated as well as tauro‐ and glyco‐conjugated bile salts. These findings corroborate preliminary studies showing in vivo that crilvastatin enhances the secretion of bile acids by stimulating the uptake and incorporation of LDL‐cholesterol by the liver.