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Amine-Containing Molecules and the Induction of an Expanded Lysosomal Volume Phenotype: A Structure-Activity Relationship Study.
Amine-Containing Molecules and the Induction of an Expanded Lysosomal Volume Phenotype: A Structure-Activity Relationship Study.
- Source :
-
Journal of Pharmaceutical Sciences . May2014, Vol. 103 Issue 5, p1572-1580. 9p. - Publication Year :
- 2014
-
Abstract
- 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]
- Subjects :
- *AMINES
*LYSOSOMES
*STRUCTURE-activity relationships
*ION traps
*FIBROBLASTS
Subjects
Details
- Language :
- English
- ISSN :
- 00223549
- Volume :
- 103
- Issue :
- 5
- Database :
- Academic Search Index
- Journal :
- Journal of Pharmaceutical Sciences
- Publication Type :
- Academic Journal
- Accession number :
- 95344879
- Full Text :
- https://doi.org/10.1002/jps.23949