FCE 27677 ([(-)N-[2,6-bis(1-methylethyl)phenyl]-N'-[(4R,5R)-2- (4-dimethylaminophenyl)-4,5 dimethyl-dioxolan-2-yl]methylurea) is a new systemically available ACAT inhibitor belonging to the class of ketalic disubstituted ureas. When tested in microsomes from rabbit intestine, aorta and liver, it inhibited the enzyme with IC50 of 9.31, 6.99 and 92.2 nM, respectively. It had no effect on plasma LCAT and intestinal cytosolic cholesterol esterases and, when tested in a tissue culture system, it did not interfere with the synthesis of cholesterol, triglycerides, and phospholipids. Enzyme inhibition kinetics indicated that FCE 27677 is a non-competitive inhibitor of the enzyme with respect to acylCoA and to cholesterol. When administered mixed to a 1.5% cholesterol and 0.5% sodium cholate-enriched diet to rats, it prevented the development of hypercholesterolemia with ED50 of 0.35 mg kg-1 day-1. Given in a single oral dose to hypercholesterolemic rats it significantly reduced both the plasma lipid levels and the hepatic cholesteryl ester content within 6 h from gavage. VLDL and LDL levels and composition were also significantly affected. Similar effects were observed when the drug was given mixed to a regular chow diet for 4 weeks to hypercholesterolemic rabbits. These results are consistent with the idea that systemically available ACAT inhibitors can affect the composition and the metabolism of the atherogenic cholesteryl ester-rich VLDL and LDL. ACAT inhibitors appear promising for the correction of dyslipoproteinemias secondary to lipoprotein overproduction, and in reducing the atherogenic index of apoB-100 containing lipoproteins.