Quantitative Modeling of Selective Lysosomal Targeting by Passive Diffusion of Xenobiotic Compounds: Model Development and Simulations for Single Cells

A model for prediction of accumulation of molecules in lysosomes by diffusive transport processes was developed. The model is based on an analytical solution of the Fick-Nernst-Planck-equation for a single cell, capturing drug transport from an external solution into various intracellular compartments: cytosol, lysosome and mitochondrium, and also lipids in these organelles. The model considers the diffusion of neutral and ionic molecules across membranes, dissociation to mono- or bivalent ions, dissolution in lipids and/or other adsorbing structures, and electrical attraction or repulsion. Input data of the chemical are log Kow, pKa(s) and valency. Based on simulation results, high and selective accumulation in lysosomes was found for lipophilic mono- and in particular bivalent bases with pKa values near 8. The model also indicates that lipophilic strong acids show moderate accumulation in lysosomes, by electrical attraction. Modeling intracellular transport may be a useful complement to molecular target-driven screening assays for facilitating design of lysosome-targeting drugs with minimal off-target interactions.
Keywords: