CHOLESTEROL-LOWERING ACTION OF HOE-402 IN THE NORMOLIPIDEMIC AND HYPERCHOLESTEROLEMIC GOLDEN SYRIAN-HAMSTER

The potent hypolipidemic activity of HOE 402 )pyrimidine-5-N-(trifluor omethylphenyl)carboxamide monohydrochloride), which was previously dem onstrated in rat and rabbit, was investigated in noncholesterol and ch olesterol fed male hamsters. In normolipidemic hamsters fed a low chol esterol chow diet containing 0.10% or 0.15% HOE 402 for 3 weeks, the p lasma total cholesterol level fell by 13% and 20% respectively, but no effect on hepatic total cholesterol content was detected. Hepatic ste rol synthesis was increased 3-fold in hamsters fed 0.15% HOE 402. In h amsters fed a chow diet containing 0.25% cholesterol for 3 weeks, the plasma cholesterol level increased to 226 mg/dl (compared to 123 mg/dl in their chow fed controls) and the liver cholesterol content was 26. 2 mg/g compared to 2.3 mg/g in the control group. However, 0.15% HOE 4 02 led to a 48% reduction acid 0.20% HOE 402 to a 80% reduction, in to tal hepatic cholesterol concentration. There was a 43% fall in plasma cholesterol level being observed with the higher HOE 402 dose. Using t he dual isotope plasma ratio method, no inhibition of intestinal chole sterol absorption by HOE 402 was found, either in the noncholesterol f ed or in the cholesterol fed hamsters. Cholesterol feeding diminished the whole LDL animal clearance to 393 +/- 17 mu l/h per 100 g animal ( control 666 +/- 81 mu l/h per 100 g). When treated with 0.20% HOE 402, the whole animal LDL clearance rate was enhanced 2.3-fold to 824 +/- 66 mu l/h per 100 g. In the hamsters fed 0.25% cholesterol alone whole liver LDL receptor activity was suppressed to 63 +/- 5%, compared to that in the untreated controls (100%). The addition of 0.20% HOE 402 t o the cholesterol enriched diet not only reversed this suppression, bu t resulted in a marked stimulation of liver receptor activity to 165 /- 15% (whole body LDL receptor activity 141 +/- 10%). These results i ndicate that HOE 402 exerts its lipid lowering effect by a more direct activation on hepatic LDL receptor activity rather than by an indirec t intestinal effect on cholesterol absorption.