EFFECT OF CRILVASTATIN, A NEW CHOLESTEROL-LOWERING AGENT, ON UNESTERIFIED LDL-CHOLESTEROL METABOLISM INTO BILE-SALTS BY RAT ISOLATED HEPATOCYTES

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 (I,DL)-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 mu M taurocholate and 50 mu M or 300 mu M 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.