Abstract

The purpose of this study was to develop a physiologically based simulation tool that is able to predict local as well as systemic bioavailability of 5-aminosalicylic acid (5-ASA)-targeted delivery formulations using the existing understanding of the transport and metabolism mechanisms of 5-ASA. The model accounts for active and passive transcellular transport (absorptive and efflux), passive paracellular transport, intestinal biotransformation, and systemic metabolism and clearance. The intestinal physiology was represented by transverse segments for ileum and proximal colon and longitudinal compartments for the microphysiology of the intestinal tissue. The tool, equipped with an optimization routine that enables tuning model parameters, was developed in Matlab and uses a user-friendly graphical interface for data input and output. Physiologic and kinetic model parameters were estimated either from literature monolayer transport studies using nonlinear curve fitting or obtained directly from the literature. 5-ASA clinical pharmacokinetic profiles of a once-daily (one 4-g/day dose) and twice-daily (two 2-g/day doses) dosing regimen were used to partially calibrate and validate the model, respectively. Simulation results showed that drug C_max in the gut mucosal layers reached a higher level and was achieved sooner than in the systemic blood level. The computed relative local bioavailability with respect to the systemic bioavailability was 0.063. With use of the model, the relative local bioavailability of different formulations can be established for fast performance verification of new preparations based on measured systemic bioavailability. These types of models play a critical role in designing such preparations and rapidly assessing their effectiveness and will foster efficient experimental designs, saving time and resources.