The EnteroHepatic Circulation (EHC) is defined as a process that is composed of a circuit of several steps including: liver metabolism, bile secretion, gut metabolism, and reabsorption from the gut back to the systemic circulation. The presence of EHC results in longer apparent drug half-lives and the appearance of multiple secondary peaks. Several empirical modeling strategies are present in the literature; however, they are generally deficient in their applicability to empirical modeling and/or physiological representation of the EHC process. The objective of the current analysis is to further develop our understanding of the application of modeling and simulation to drugs undergoing EHC. We propose a gallbladder-based model that provides a more physiological representation of the EHC process. The model was used in a sensitivity analysis to evaluate the effect of the extent of EHC on the pharmacokinetic profile and non-compartmental analysis (NCA) calculations. Stochastic Simulation and Estimation (SSE) analysis was conducted to compare parameter estimates from several literature EHC models following a single dose of a drug undergoing EHC. The proposed model was applied in a population pharmacokinetic analysis of unbound mycophenolic acid (MPA), total MPA, mycophenolic acid glucuronide (MPAG) and acyl-MPAG. Finally, a quantitative evaluation of the MPA exposure-response relationship was performed by building a logistic model that described the relationships between total MPA, unbound MPA and acyl-MPAG exposure variables and the probability of acute rejection and leukopenia.