CI-976, a new trimethoxy
fatty acid anilide, is a potent and specific inhibitor of liver and intestinal
acyl coenzyme A:
cholesterol acyltransferase (ACAT) in vitro. Several in vivo approaches were used to determine the efficacy and sites of action of this compound in rats.
CI-976 decreased non-
high density lipoprotein (
HDL)-cholesterol and increased
HDL-cholesterol in rats with pre-established
dyslipidemia. High performance gel chromatographic separation of plasma
lipoproteins also revealed that
CI-976, but not CL 277,082, lowered
low density lipoprotein (
LDL)-cholesterol and elevated
HDL-cholesterol. Bay o 2752,
octimibate,
melinamide, and SaH 58-035 were all less potent in vivo compared to
CI-976 and CL 277,082, and
CI-976 produced the greatest decrease in liver
cholesteryl esters. Subcutaneous (SC) administration of
CI-976 was also efficacious in
cholesterol-fed animals. In
sucrose-fed rats, oral and SC
CI-976 administration potently lowered plasma
triglycerides. Hepatic
cholesteryl ester accumulation in the
ethinyl estradiol-treated rat was also diminished by orally administered
CI-976. ACAT activity and
cholesteryl ester mass were dose-dependently decreased in the livers from
cholesterol-fed rats treated with
CI-976, suggesting a direct effect on the liver. In both hypercholesterolemic and hypertriglyceridemic models,
CI-976 also decreased plasma
apoB concentrations. In other experiments radiolabeled
CI-976 accumulated in the liver after multiple doses. Time-dependent changes in biliary
lipid and
bile acid secretion suggested that free
cholesterol did not accumulate in the liver but instead was excreted as such or as
bile acid. Finally, inhibition of endogenous and exogenous intestinal
cholesterol absorption was demonstrated using several in vivo techniques. The combined data strongly supports the hypothesis that orally administered
CI-976 inhibits both intestinal and hepatic ACAT, and that both of these
enzymes may be determinants of plasma
lipid concentrations in the rat.