Crilvastatin

. The objective of this study was to compare in cultured human hepatocytes or Hep G2 cells, changes in the fate of unesterified low density lipoprotein (LDL)‐cholesterol induced by crilvastatin, a new cholesterol lowering drug and a reference statin, simvastatin.. The experiments were carried out for 20 h, each well contained 4.2 × 105/cm2 Hep G2 cells or 0.5 × 105/cm2 human hepatocytes, 130 μm ursodeoxycholate, 0.68 μCi or 1.59 μCi unesterified human [14C]‐LDL‐cholesterol, crilvastatin or simvastatin at 0 or 50 μm (both cell types) or 300 μm (Hep‐G2 cells). Incubation with the two drugs resulted in increased amounts of unesterified [14C]‐LDL‐cholesterol taken by the two cell types, compared to control.. Crilvastatin 50 μm led to significantly higher quantities of [14C]‐glyco‐ and [14C]‐tauro‐conjugated bile salts, compared to simvastatin. Statins reduced the apo B100 level secreted by the two cell types (simvastatin) or human hepatocytes (crilvastatin). Crilvastatin enhanced both the level of apo A1 secreted by the Hep G2 cells and the level of APF, a high density lipoprotein (HDL) and biliary apoprotein.. Crilvastatin not only acts by stimulating LDL‐cholesterol uptake by hepatocytes, but also by enhancing the catabolism of LDL‐cholesterol in bile salts and probably by stimulating HDL and/or bile component secretion. Such a mechanism was not previously described for HMG CoA reductase inhibitors. Our results on APF show that this apoprotein could be considered also as an indicator of changes in bile and/or HDL compartments.. The human hepatocyte model appeared to be a suitable and relevant model in the pharmacological***metabolic experiments carried out in this study. It led to more consistent data than those obtained with Hep G2 cells.

Crilvastatin is a new drug from the pyrrolidone family, which acts as a non-competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. The long-term effects of oral crilvastatin treatment (200 mg per day per kg body weight for 4 and 10 weeks) were investigated on in vivo cholesterogenesis in male adult normocholesterolemic (SW) and genetically hypercholesterolemic (RICO) rats. In both strains of rats, the treatment had no effect on the plasma cholesterol level, but efficiently inhibited cholesterol synthesis in liver and intestine, as shown by the decreased incorporation of exogenous [14C]acetate into hepatic (3.5-fold in SW, 1.7-fold in RICO rats) and intestinal (2.5-fold in SW, 3.3-fold in RICO rats) sterols. In RICO rats in which the dietary cholesterol absorption coefficient was two-fold lower in treated (38%) than in untreated (78%) rats, this drug reduced intestinal cholesterol absorption. As a result, the total plasma cholesterol input (absorption + synthesis), measured by isotope analysis in RICO rats, was markedly lower in treated (11.3 mg per day) than in untreated animals (28.8 mg per day).