A Parent-Metabolite Middle-Out PBPK Model for Genistein and Its Glucuronide Metabolite in Rats: Integrating Liver and Enteric Metabolism with Hepatobiliary and Enteroluminal Transport to Assess Glucuronide Recycling.

: Glucuronide recycling in the gut and liver profoundly affects the systemic and/or local exposure of drugs and their glucuronide metabolites, impacting both clinical efficacy and toxicity. This recycling also alters drug exposure in the colon, making it critical to establish local concentration for drugs targeting colon (e.g., drugs for colon cancer and inflammatory bowel disease). : In this study, a parent-metabolite middle-out physiologically based pharmacokinetic (PBPK) model was built for genistein and its glucuronide metabolite to estimate the systemic and local exposure of the glucuronide and its corresponding aglycone in rats by incorporating UDP-glucuronosyltransferase (UGT)-mediated metabolism and transporter-dependent glucuronide disposition in the liver and intestine, as well as gut microbial-mediated deglucuronidation that enables the recycling of the parent compound. : This parent-metabolite middle-out rat PBPK model utilized in vitro-to-in vivo extrapolated (IVIVE) metabolic and transporter clearance values based on in vitro kinetic parameters from surrogate species, the rat tissue abundance of relevant proteins, and saturable Michaelis-Menten mechanisms. Inter-system extrapolation factors (ISEFs) were used to account for transporter protein abundance differences between in vitro systems and tissues and between rats and surrogate species. Model performance was evaluated at multiple dose levels for genistein and its glucuronide. Model sensitivity analyses demonstrated the impact of key parameters on the plasma concentrations and local exposure of genistein and its glucuronide. Our model was applied to simulate the quantitative impact of glucuronide recycling on the pharmacokinetic profiles in both plasma and colonocytes. : Our study underlines the importance of glucuronide recycling in determining local drug concentrations in the intestine and provides a preliminary modeling tool to assess the influence of transporter-mediated drug-drug interactions on glucuronide recycling and local drug exposure, which are often misrepresented by systemic plasma concentrations.