DEHA PBPK model in rats_raw data

To develop a physiologically based pharmacokinetic (PBPK) model for di(2-ethylhexyl) adipate (DEHA) and its metabolites in rats, the kinetics of the adipates were investigated through in vitro experiments with rat-derived materials and in vivo studies in rats. In in vitro studies using homogenates from nine rat organs, esterase(s) appeared to contribute significantly to the instability of DEHA and its primary metabolite mono(2-ethylhexyl) adipate (MEHA), while lipases also appeared to be involved in the degradation of DEHA. The sum of all observed in vitro metabolic activities attributable to tissue elimination accounted for the majority of in vivo systemic clearance of DEHA/MEHA. DEHA was found to be completely converted to MEHA, whereas the fraction of the MEHA dose converted to secondary metabolites was markedly low (i.e., < 0.2%), as determined in both the in vivo and in vitro experiments. Following oral administration to rats, DEHA was estimated to be absorbed almost equally to the portal-hepatic and the lymphatic routes. The established PBPK model captured the concentration profiles of the adipates in plasma/lymph after intravenous/oral administration of the adipates to rats. Current PBPK model may be relevant for reverse dosimetry to estimate human exposure to DEHA under typical exposure scenarios.