Binding to plasma lipoproteins of chlorophenoxyisobutyric, tibric and nicotinic acids and their esters: its significance for the mechanism of lipid lowering by clofibrate and related drugs.

The binding of chlorophenoxyisobutyric (CPIB), tibric (TA) and nicotinic (NA) acids and CPIB ethyl ester (Clofibrate), TA and NA isopropyl esters (TAPE and NAPE) to human lipoproteins of low density of different classes (LDL2, LDL1 and VLDL) and high density (HDL) were studied by equilibrium dialysis and Sephadex gel filtration. Clofibrate and TAPE bound strongly to lipoproteins, but their acids, CPIB and TA and also NA and NAPE, did not bind. In the same experimental conditions, Clofibrate and TAPE bound only weakly to human serum albumin (HSA) and CPIB bound to HSA with a Ka of 3.3 X 10(5) M(-1) for 1 site of high affinity. The Clofibrate and TAPE bound to lipoproteins did not dissociate either during dialysis or during filtration on Sephadex G 25. The binding percentage remained constant for all drug concentrations studied, and the molar ratio of bound drug rose linearly with increasing concentrations. This suggests that the interaction may be irreversible, and there is some evidence that binding may induce irreversible changes in the lipoprotein molecules. These results, and those already found in experiments made with three other drugs related to Clofibrate, lead to the proposal that in their interaction with lipoproteins, the phenyl groups are necessary and the esterification is contributory. The possible role of this interaction in the lipid-lowering effect of the drugs is discussed with special reference to their possible implication in lipoprotein synthesis within the intestinal and hepatic cells.