Drug elimination via glucuronidation pathway is a complex process involving glucuronide excretion. Glucuronide excreted into the gut lumen either directly from the enterocytes or from the hepatobiliary route can be recovered back to the precursor (aglycone) through bacteria-mediated hydrolysis. As a result, the pharmacokinetics [e.g., plasma terminal half-life (T 1/2 )] of aglycone might be altered. Here, impact of intestinal glucuronide hydrolysis on the pharmacokinetics of aglycone is evaluated using physiologically based pharmacokinetic (PBPK) models with liver and/or intestine as eliminating organs. It is found that compared with its absence, the presence of intestinal glucuronide hydrolysis leads to increases in the oral systemic bioavailability (F sys ) of aglycone. The magnitude of fold increase is positively correlated with the level of metabolism, as metabolic clearance mainly contributes to recycled amount of glucuronide. Although F sys is independent of the glucuronide efflux in a traditional model and a segregated-flow model of the intestine, dependence of F sys on the glucuronide efflux can be observed in a segmental segregated-flow model of the intestine and whole-body PBPK models. Interestingly, when the ratio of apical versus basolateral efflux intrinsic clearances (of glucuronide) is fixed, their effects on the intestinal bioavailability and F sys cease to exist. In addition, glucuronide hydrolysis can lead to a significantly delayed elimination of the aglycone as evidenced by a prolonged (e.g., a 2.1-fold increase) T 1/2 . Surprisingly, when a pharmacokinetic profile for aglycone is simulated with a flat terminal portion (a reflection of the experimental observations), changes in the aglycone bioavailabilities are limited (i.e., β€1.3-fold). In conclusion, this study explores the possible role of intestinal glucuronide hydrolysis in the disposition of aglycone via simulations utilizing various PBPK models. The mechanistic observations should be helpful to better understand the complex glucuronidation in vivo.