Perspectives on Intracellular Storage and Transport of Cationic-Lipophilic Drugs

The intracellular storage of CLD may manifest morphologically by various types of alterations. Combinations of these types may occur. Chemical alterations associated with storage are changes (primarily increases) in content of phospholipid, glycosaminoglycans and monosaccharides, and various combinations of these alterations may occur. There is no apparent correlation between the induced types of morphologic and chemical alterations. Storage of CLD is linked to the cytoplasmic acidic vesicular compartment, which includes endocytic, transport, Golgi, and secretory vesicles in addition to lysosomes. CLD-induced alterations in phospholipid and saccharide may play a role in intracellular storage and transport, especially with respect to cytoplasmic acidic vesicular trafficking and GPI anchors. The role of the cationic moiety in storage of CLD and the physicochemical features of this moiety for highly potent inducers of clear cytoplasmic vacuoles have been delineated. The lipophilic moiety is important for induction of biochemical alterations that accompany storage of CLD. The physicochemical properties of the lipophilic moiety, including the importance of the degree of lipophilicity, as determinant in induction of these biochemical alterations, remain to be elucidated. Not all CLD are stored in cells. Storage of CLD with its associated morphologic and biochemical alterations may or may not be a sign of toxicity. If CLD induce toxicity, this may be caused by other mechanisms not related directly to intracellular storage. Delineation of structure-activity relationships associated with storage enabled synthesis of new cardiac antiarrhythmic drugs. The association of CLD storage and absence of toxicity with intracellular transport and secretion is an extension beyond the concept of lysosomotropic agents (28). An interdisciplinary approach using a variety of investigative methods would be advantageous to further research on intracellular storage and transport of CLD; in this context, cultured cells are a highly advantageous research system.