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 _ raw data

Di(2-ethylhexyl) adipate (DEHA), a widely used plasticizer, is a biocompatible ester that has been considered forpotential application as a pharmaceutical excipient. We developed a physiologically-based pharmacokinetic(PBPK) model for DEHA and its primary metabolite, mono(2-ethylhexyl) adipate (MEHA), using a robust bottom-up modeling strategy in rats. In vitro metabolism studies of the adipates, conducted with homogenates from nine rat organs, indicated that esterase(s) appeared to play significant roles in the instability of both adipates with vascular lipases also potentially contributing to the DEHA metabolism. When extrapolating to in vivoclearance, we accounted for physiologically-based, circulatory topology-driven muti-tissue metabolism. The resulting PBPK model reproduced the rapid initial kinetic phase and resolved critical discrepancies, namely, the atypical metabolite formation fraction of MEHA and the implausible initial volume of DEHA, observed withstandard moment analysis. Following oral administration of DEHA, a distinct and reproducible double-peak phenomenon was observed in the plasma concentration-time profile. Given the highly lipophilic nature of DEHA, lymphatic absorption was explicitly modeled and parameterized using in vivo mesenteric lymph data. The model estimated approximately equal contributions of portal-hepatic and lymphatic pathways to the intestinal absorption of DEHA. The current model successfully predicted the plasma concentration-time profiles of DEHA and MEHA following both intravenous and oral administration, supporting the validity of the model. Collectively, this framework may provide a template that can be extended to predict the pharmacokinetics of lipophilic ester prodrugs or excipients.