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Enterohepatic circulation (EHC) is a complex process where drugs undergo secretion and reabsorption from the intestinal lumen multiple times, resulting in pharmacokinetic profiles with multiple peaks. The impact of EHC on area under the curve (AUC) has been a topic of extensive debate, questioning the suitability of conventional AUC estimation methods. Moreover, a universal model for accurately estimating AUC in EHC scenarios is lacking. To address this gap, we conducted a simulation study evaluating five empirical models under various sampling strategies to assess their performance in AUC estimation. Our results identify the most suitable model for EHC scenarios and underscore the critical role of meal-based sampling strategies in accurate AUC estimation. Additionally, we demonstrate that while the trapezoidal method performs comparably to other models with a large number of samples, alternative models are essential when sample numbers are limited. These findings not only illuminate how EHC influences AUC but also pave the way for the application of empirical models in real-world drug studies. [ABSTRACT FROM AUTHOR]