The pharmacokinetics of EnteroHepatic Circulation

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.