The results of cell monolayer permeation experiments are often affected by concentration dependent cellular processes, such as active transport and metabolism. The rigorous analysis of the concentration dependence of these processes is often limited by the lack of knowledge of the actual concentration at the site of action because the measurement of the local concentration is seldom feasible. However, the local concentrations can be estimated if the rates into and out of a particular location are known. Thus, an insight into the distribution of the permeation resistance in the in vitro cell monolayer permeation experiments would enable the estimation of local concentrations during the permeation experiments and, consequently, a more thorough analysis of the concentration dependent processes involved in the transepithelial transfer of compounds. In this study, a compartmental model was constructed applicable for dissecting the roles of apical and basal side aqueous boundary layers and the cell membranes in the total permeation barrier for weakly acidic and basic compounds. The model was applied for the analysis of the Caco-2 permeation data of three high permeability compounds, propranolol, metoprolol and ibuprofen. Furthermore, the effects of extracellular pH and the agitation conditions on the local concentrations of these compounds were evaluated.
Adrenergic beta-Antagonists Anti-Inflammatory Agents, Non-Steroidal