Physiologically Based Pharmacokinetic Modeling of Di(2-ethylhexyl) Adipate and Its Primary Metabolite, Mono(2-ethylhexyl) Adipate, in Rats, Incorporating Circulatory Topology-Based Multi-Tissue Metabolism and Lymphatic Absorption.

Background/Objectives: Di(2-ethylhexyl) adipate (DEHA), a biocompatible ester plasticizer, has gained interest as a potential pharmaceutical excipient, yet its pharmacokinetics remain poorly characterized. This study aimed to develop a physiologically based pharmacokinetic (PBPK) model for DEHA and its primary metabolite, mono(2-ethylhexyl) adipate (MEHA), in rats by integrating in vitro, in vivo, in silico, and physiological data. Methods: In vitro hydrolysis was evaluated across tissues using bis-(p-nitrophenyl) phosphate (BNPP) to distinguish BNPP-sensitive and -insensitive metabolism, and tissue-specific clearances were extrapolated to the whole body using a circulatory topology-based framework accounting for sequential extraction across tissues, venous blood, and lungs. Results: Both adipates underwent rapid BNPP-sensitive hydrolysis across multiple tissues, whereas DEHA additionally exhibited BNPP-insensitive metabolism. The framework yielded reasonable estimates of the observed arterial clearance in vivo. Following oral administration, DEHA showed a reproducible double-peak plasma profile, with lymphatic transport identified as the predominant absorption route responsible for the prolonged terminal phase. The final model adequately reproduced the plasma and mesenteric lymph concentration-time profiles of DEHA and MEHA following both intravenous and oral administration. Conclusions: By integrating multi-tissue metabolism, circulatory topology, and lymphatic absorption, this study provides a quantitative framework applicable to rapidly hydrolyzed, highly lipophilic ester compounds, including pharmaceutical excipients and ester prodrugs.