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Many weakly basic amine-containing compounds have a strong propensity to become highly concentrated in lysosomes by virtue of an ion-trapping-type mechanism; the substrates for this are referred to as lysosomotropic. We have previously shown that many lysosomotropic drugs can produce a significant expansion in the apparent volume of lysosomes, which can ultimately result in an intracellular distribution-based drug-drug interaction. In this study, we have systematically evaluated the physicochemical and structural features of weakly basic molecules that correlate with their ability to induce an expanded lysosomal volume phenotype ( ELVP) in cultured human fibroblasts. By quantitatively evaluating the cellular accumulation of Lysotracker Red, a fluorescent lysosomotropic probe, the volume of the lysosomal compartment was determined. We specifically explored the influence that lysosomotropism, molecular size, and amphiphilicity had on a molecule's ability to induce an ELVP. The capacity of these molecules to intercalation into biological membranes was also evaluated using a red blood cell hemolysis assay. The present results suggest that a molecule's potency in eliciting an ELVP is influenced by lysosomotropism, amphiphilicity, and its ability to intercalate into biological membranes. Despite being highly lysosomotropic, low-molecular-weight, nonaromatic amines failed to cause an ELVP at all concentrations evaluated. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:1572-1580, 2014 [ABSTRACT FROM AUTHOR]