AUTHOR=McNally Kevin , Sams Craig , Loizou George 

TITLE=Development, testing, parameterisation, and calibration of a human PBK model for the plasticiser, di (2-ethylhexyl) adipate (DEHA) using in silico, in vitro and human biomonitoring data

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 14 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1165770

DOI=10.3389/fphar.2023.1165770

ISSN=1663-9812

ABSTRACT=Introduction
A physiologically based pharmacokinetic model for di (2-ethylhexyl) adipate (DEHA) based on a refined model for di-(2-propylheptyl) phthalate (DPHP) was developed to interpret the metabolism and biokinetics of DEHA following a single oral dosage of 50 mg to two male and two female volunteers. 
Methods
The model was parameterized using in vitro and in silico methods such as, measured intrin-sic hepatic clearance scaled from in vitro to in vivo and algorithmically predicted parameters such as plasma unbound fraction and tissue:blood partition coefficients (PCs). Calibration of the DEHA model was achieved using concentrations of specific downstream metabolites of DEHA excreted in urine. The total fractions of ingested DEHA eliminated as specific me-tabolites were estimated and were sufficient for interpreting the human biomonitoring data. 
Results
The specific metabolites of DEHA, mono-2-ethyl-5-hydroxyhexyl adipate (5OH-MEHA), mono-2-ethyl-5-oxohexyl adipate (5oxo-MEHA), mono-5-carboxy-2-ethylpentyl adipate (5cx-MEPA) only accounted for ~ 0.45% of the ingested DEHA. Importantly, the measure-ments of adipic acid, a non-specific metabolite of DEHA, proved to be important in model calibration. 
Discussion
The very prominent trends in the urinary excretion of the metabolites, 5cx-MEPA and 5OH-MEHA allowed the important absorption mechanisms of DEHA to be modelled. The model should be useful for the study of exposure to DEHA of the general human population.