Radioiodinated Molecules as Markers for Studying the Importance of Lipoproteins in Drug Disposition.

Abstract

Lipids are transported from one tissue to another through the blood by lipoproteins, water-soluble complexes composed of a lipid core surrounded by surface phospholipids and apoproteins. Once these macromolecular complexes reach the tissue, they are taken up by nonspecific or receptor-mediated endocytosis. The manner whereby lipophilic drugs may participate in such processes is not well documented. Accordingly, the two goals of this research project were: (1) to study the role of lipoproteins in drug disposition, and (2) to examine their potential as site-specific delivery vehicles to the adrenal gl and . Two radioiodinated probes, ('125)I-cholesteryl oleate (('125)I-CO), a derivative of a natural constituent of lipoproteins, and 2-(2-chlorophenyl),2-(4{('125)I}-iodophenyl)-1,1-dichloroethane (('125)I-DDD), an analog of the adrenolytic drug o,p'-DDD (Mitotane), were selected for these studies. In vivo and in vitro techniques were utilized to associate these probes with rat high density lipoproteins (HDL). Tissue distribution studies indicated that prior incorporation of ('125)I-CO into rat HDL increased the uptake of ('125)I-CO by rat adrenal, which was dramatically enhanced when this preparation was administered to animals made hypolipidemic with 4-aminopyrazolo-(3,4-d)-pyrimidine (4-APP). Acetylation of HDL labeled with ('125)I-CO provided evidence that the observed uptake into the adrenal was via a receptor-mediated process. In contrast with these results, prior association of ('125)I-DDD with rat HDL failed to alter the ability of this compound to accumulate in adrenal tissue of normal or hypolipidemic animals. Gel filtration and polyacrylamide gel electrophoresis were utilized to examine the stability of the association of ('125)I-CO and ('125)I-DDD with rat HDL. These results suggested that ('125)I-CO was associated with the lipophilic core of HDL, whereas ('125)I-DDD appeared to be partially associated with the surface components of HDL. Saturation of surface components of HDL with stable o,p'-DDD offered data to suggest that this binding to apoproteins may disrupt the normal receptor-mediated uptake process. This is the first evidence that lipophilic drugs may actually alter the metabolic fate of lipoproteins.