Studies on the mechanism of action of probucol.

Earlier clinical studies suggested that probucol lowers plasma levels of low density lipoprotein (LDL) by increasing the rate of its removal. The drug has been shown to be effective in patients lacking the LDL receptor and, more recently, in LDL receptor-deficient rabbits. These latter studies showed that probucol increased the fractional catabolic rate of LDL by 40% to 50%. This finding in a receptor-deficient model implies that probucol can enhance the removal of LDL cholesterol by alternative pathways. Because the same enhanced removal was seen when LDL from probucol-treated rabbits was injected into untreated rabbits, it appears that the drug somehow alters the metabolic properties of the LDL itself rather than the metabolic behavior of the tissues of treated animals. Whether or not this mechanism explains the action of probucol in man remains to be determined. It has been postulated that the oxidative modification of LDL might contribute to atherogenesis by facilitating lipid accumulation in macrophages (foam cells) and by inhibiting macrophage motility. LDL resists oxidative modification, however, when probucol is added to in vitro incubations or when the LDL itself is isolated from probucol-treated patients. These findings lay the groundwork for evaluating the possible in vivo significance of LDL oxidation.