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Review
. 2019 Oct;35(4):295-301.
doi: 10.5487/TR.2019.35.4.295. Epub 2019 Oct 15.

Extrapolation of Hepatic Concentrations of Industrial Chemicals Using Pharmacokinetic Models to Predict Hepatotoxicity

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Free PMC article
Review

Extrapolation of Hepatic Concentrations of Industrial Chemicals Using Pharmacokinetic Models to Predict Hepatotoxicity

Hiroshi Yamazaki et al. Toxicol Res. .
Free PMC article

Abstract

In this review, we describe the absorption rates (Caco-2 cell permeability) and hepatic/plasma pharmacokinetics of 53 diverse chemicals estimated by modeling virtual oral administration in rats. To ensure that a broad range of chemical structures is present among the selected substances, the properties described by 196 chemical descriptors in a chemoinformatics tool were calculated for 50,000 randomly selected molecules in the original chemical space. To allow visualization, the resulting chemical space was projected onto a two-dimensional plane using generative topographic mapping. The calculated absorbance rates of the chemicals based on cell permeability studies were found to be inversely correlated to the no-observed-effect levels for hepatoxicity after oral administration, as obtained from the Hazard Evaluation Support System Integrated Platform in Japan (r = -0.88, p < 0.01, n = 27). The maximum plasma concentrations and the areas under the concentration-time curves (AUC) of a varied selection of chemicals were estimated using two different methods: simple one-compartment models (i.e., high-throughput toxicokinetic models) and simplified physiologically based pharmacokinetic (PBPK) modeling consisting of chemical receptor (gut), metabolizing (liver), and central (main) compartments. The results obtained from the two methods were consistent. Although the maximum concentrations and AUC values of the 53 chemicals roughly correlated in the liver and plasma, inconsistencies were apparent between empirically measured concentrations and the PBPK-modeled levels. The lowest-observed-effect levels and the virtual hepatic AUC values obtained using PBPK models were inversely correlated (r = -0.78, p < 0.05, n = 7). The present simplified PBPK models could estimate the relationships between hepatic/plasma concentrations and oral doses of general chemicals using both forward and reverse dosimetry. These methods are therefore valuable for estimating hepatotoxicity.

Keywords: Caco-2 permeability; Hepatotoxicity; Lowest-observed-effect level; No-observed-effect level; PBPK modeling.

Conflict of interest statement

CONFLICT OF INTEREST There is no conflict of interest.

Figures

Fig. 1
Fig. 1
Apparatus for intestinal epithelial permeability testing. The Caco-2 cell monolayer system was used for a variety of general chemicals.
Fig. 2
Fig. 2
Coordinate values in a two-dimensional plane illustrating a variety of chemical structures. The density of the circles indicates apparent permeability values of the chemicals across an intestinal epithelial cell monolayer.
Fig. 3
Fig. 3
The inverse relationship between hepatic NOEL values of the industrial chemicals reported in a rat database and the apparent permeability data measured using Caco-2 permeability assays.
Fig. 4
Fig. 4
Schematic representations of one-compartment (A) and PBPK (B) models to simulate virtual oral administrations of the chemicals. F, Fa, and Fg: bioavailability, k1, and ka: absorption constants, V, V1, and Vh: volumes of distribution, kel: elimination constant, and CLh and CLr: clearances.

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