F 12511, a novel ACAT inhibitor, and atorvastatin regulate endogenous hypercholesterolemia in a synergistic manner in New Zealand rabbits fed a casein-enriched diet

F 12511, a novel ACAT inhibitor, lowers plasma cholesterol levels in New Ze aland rabbits fed a cholesterol-free casein-rich diet. In rabbits endogenou s hypercholesterolemia pre-established for 8 weeks was used to compare trea tments with F 12511 and atorvastatin for a further 8-week period, and to de termine whether both agents act synergistically. F 12511 appears to be 3-4- fold more potent than atorvastatin in reducing total plasma cholesterol (ac tive doses ranging from 0.16 to 2.5 and from 1.25 to 10 mg/kg per day, resp ectively) while the hypocholesterolemic efficacy of both compounds at 2.5 m g/kg per day amounted to 70 and 45%, respectively. A reduction by as much a s 75% of esterified cholesterol in liver mediated by F 12511 could account for the decrease of plasma VLDL, LDL and apo B-100, whereas a reduction of the LDL production rate has been described as the main mechanism underlying the atorvastatin effect. F 12511 modified adrenal cholesterol balance only at the largest dose studied. In a further experiment the co-administration of threshold doses of F 12511 and atorvastatin (0.63 and 1.25 mg/kg per da y, respectively) lowered plasma total cholesterol and apo B-100 containing lipoproteins to a greater extent and more rapidly than either agent alone. In the liver a decrease by atorvastatin in free cholesterol substrate for A CAT may amplify the effect of F 12511 on cholesteryl ester content leading to a diminution, in at least an additive manner, of the assembly and secret ion of atherogenic lipoproteins in New Zealand rabbits which have developed an endogenous hypercholesterolemia. Thus, the combination of the ACAT inhi bitor F 12511 with atorvastatin can represent a better approach than either agent alone to regulate lipoprotein metabolism in certain pathophysiologic al situations. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.