PLASMA-CHOLESTEROL REDUCING EFFECT OF FR129169, A NOVEL ACYL-COA-CHOLESTEROL ACYLTRANSFERASE INHIBITOR, IN THE RAT

FR129169 (FR) (N-(1,2-diphenylethyl)-2-octyloxyphenylacetamide) has be en found to inhibit acyl-CoA:cholesterol acyltransferase (ACAT) activi ties in intestinal microsomes of rats and rabbits and the liver homoge nate of rats with IC50 values of around 1.0 x 10(-7) M. The inhibitory activity was 2-3 times more potent than that of CI976 (CI). When FR i n a dose of 10 mg/kg/day was administered as a dietary admixture, plas ma cholesterol levels were normalized in rats fed a high cholesterol d iet, but lower doses of FR had no effect. Similar results were obtaine d in the rats treated with CI. The ex vivo study where hepatic ACAT ac tivity was measured after oral dosing of the two inhibitors revealed t hat ACAT activity was significantly reduced in rats treated with FR in a dose of 10 mg/kg/day, while CI reduced the activity at lower doses such as 0.1 and 1 mg/kg/day. Since FR was not orally absorbed, it is s peculated that the inhibitory activity of FR on hepatic ACAT in the ex vivo study results from the reduction of plasma cholesterol levels. T hese results suggest that FR exerted cholesterol-lowering activity mai nly through inhibition of intestinal ACAT activity. The significance o f intestinal ACAT inhibition by FR for therapeutic treatment of hyperc holesterolemia is discussed.