Abstract

Purpose: To develop a mechanistic mathematical model for analysis of in vitro permeability assays that accounts for all mechanisms contributing to observed apparent permeability: passive paracellular and transcellular diffusion, ionization effects, carrier-mediated transport, and metabolism, as well as drug accumulation in membranes and some intracellular compartments (e.g., lysosomes). The model was applied to analyze the effects of lysosomal trapping on the measured apparent permeability of propranolol.

Methods: MembranePlus™ (Simulations Plus, Inc.) was used to analyze the concentration-time profiles in donor and receiver compartments after apical and basolateral administration of ibuprofen, testosterone and propranolol alone, as well as propranolol in the presence of bafilomycin [1]. The physicochemical properties of propranolol, ibuprofen, and testosterone were predicted by ADMET Predictor™ 6.0 (Simulations Plus, Inc.). The contribution of paracellular diffusion for each drug was estimated from drug properties and the experimental setup. Parameters accounting for passive transcellular diffusion and membrane/lysosomal accumulation were fitted to the propranolol, ibuprofen, and testosterone alone data. This basic model was then applied to explore the effect of bafilomycin on lysosomal pH and the subsequent change in propranolol accumulation in lysosomes. The model includes various effects of the experimental setup (i.e., shaking rate, solvent pH, filter support, sampling effects, etc.) on measured apparent permeability.

By Ke X. Szeto, Viera Lukacova, John DiBella, Walter S. Woltosz, and Michael B. Bolger