Effects of clofibrate, cholestyramine, zanchol, probucol, and AOMA feeding on hepatic and intestinal cholesterol metabolism and on biliary lipid secretion in the rat

Utilizing newer techniques for measuring rates of cholesterol synthesis, the effects of clofibrate, cholestyramine, zanchol, probucol, and AOMA (a copolymer of maleic acid and an α-olefin chain of 18 carbons) on hepatic and intestinal cholesterol metabolism and on biliary lipid secretion in the rat were examined. Under conditions of isocaloric feeding, female rats were administered a fixed amount of these drugs each day for 14 days. In one set of experiments the rats were killed and rates of hepatic and intestinal cholesterol synthesis and tissue cholesterol levels were measured. In a second set of studies the rats were subjected to total biliary diversion for 2 hr and rates of biliary lipid secretion were determined. Plasma cholesterol concentrations were measured in all animals. Neither AOMA nor cholestyramine had any effect on plasma cholesterol levels or biliary lipid secretion, but both markedly enhanced intestinal cholesterol synthesis. Cholestyramine also increased hepatic cholesterol synthesis. Clofibrate significantly decreased plasma cholesterol levels, whereas zanchol had the opposite effect. Both clofibrate and zanchol increased liver size and bile secretion rates but lowered biliary lipid concentrations; however, total biliary lipid output was unchanged. Total hepatic cholesterol synthesis in clofibrate-fed animals was similar to that in the controls, but in zanchol-fed animals it was approximately doubled. Neither clofibrate nor zanchol had any effect on intestinal cholesterol synthesis. Probucol dramatically lowered plasma cholesterol levels but had no effect on the other parameters measured. None of the drugs was effective in altering the molar percentage of cholesterol in bile despite the diversity of metabolic changes which occurred. These studies point up the many diverse metabolic effects of these drugs, some of which are clinically useful in lowering plasma cholesterol levels, and delineate the marked dissociations that occur between rates of cholesterol synthesis, tissue cholesterol levels, and plasma cholesterol concentrations.