Lipophilic Cationic Drugs Increase the Permeability of Lysosomal Membranes in a Cell Culture System

摘要: Lysosomes accumulate many drugs several fold higher compared to their extracellular concentration. This mechanism is believed be responsible for pharmacological effects. So far, uptake and release kinetics are largely unknown interactions between concomitantly administered often provoke mutual interference. In this study, we addressed these questions in a cell culture model. The molecular lysosomal was analyzed by live fluorescence microscopy SY5Y cells using four (amantadine, amitriptyline, cinnarizine, flavoxate) with different physicochemical properties. Drugs lipophilicity accumulated more extensively within lysosomes, whereas pKa value associated rapid uptake. drug-induced displacement of LysoTracker neither caused elevation intra-lysosomal pH, nor increased volume. We extended our previously developed numerical single model introducing dynamic feedback mechanism. empirical data were good agreement the results obtained from experimental lead conclusion that accumulation lipophilic xenobiotics enhances membrane permeability. Manipulation permeability might useful overcome, example, multi-drug resistance altering subcellular drug distribution. J. Cell. Physiol. 224:152–164, 2010 © Wiley-Liss, Inc.