OBJECTIVE Strategies for modeling the enterohepatic circulation (EHC) process reported in the literature vary; however, gallbladder-based models currently provide the best physiological representation of the process. Regardless, the addition of a gallbladder to the model does not fully depict the physiology of EHC. A more physiological gallbladder-based EHC model is needed. This model should take into account a physiological representation of the bile secretion, gallbladder filling and emptying, the duration of gallbladder emptying, and irregular mealtimes. Considering all of these factors, the objectives of the present analysis were to propose a gallbladder-based EHC model and then to use that model to perform sensitivity analyses evaluating the effect of the extent of EHC on the pharmacokinetic profile and noncompartmental analysis (NCA) calculations. METHODS A gallbladder-based model that describes the EHC process was developed and used to perform determinant simulations assuming various degrees of EHC. Next, these simulations were compared to evaluate the effect of the EHC on the pharmacokinetic profiles of orally administered drugs. The influence of the EHC process on the NCA calculations was determined while assuming two sampling schemes that differed in the times at which sampling was performed in relation to meal times. RESULTS The presence of EHC results in nonlinearity in the system and changes the pharmacokinetic profile, affecting the maximum concentration (Cmax), time to Cmax (Tmax), and half-life estimates. Comparison of the results obtained using the two sampling schemes for a drug undergoing various degrees of EHC demonstrated a significant influence of the selected sampling times on the NCA estimations. Bias in the NCA calculations was also dependent on the sampling times used. CONCLUSIONS Caution should be taken when designing clinical studies for drugs that undergo EHC. It may be essential to consider the timing of meals when planning pharmacokinetic studies and defining sampling times. The period over which samples are taken needs to be extended as compared to that traditionally used with other drugs. Future studies that attempt to identify the best sampling strategies in the presence of EHC are needed.