Dataset Information

Comparative analysis of Rapid Equilibrium Dialysis (RED) and solid phase micro-extraction (SPME) methods for In Vitro-In Vivo extrapolation of environmental chemicals.

ABSTRACT: In vitro to in vivo extrapolation (IVIVE) is a critical component of the efforts to prioritize and assess environmental chemicals using high-throughput in vitro assays. The plasma unbound fraction (Fub) is a key toxicokinetic parameter in IVIVE, and is usually measured via the Rapid Equilibrium Dialysis (RED) assay widely used for pharmaceuticals. However, pharmaceuticals have a narrower range of physicochemical properties than environmental chemicals. Motivated by the observation that high LogKOW compounds appeared to have disproportionately low Fub measurements using RED, we added a protein-free control in order to verify equilibration to 100% unbound in the absence of proteins. We found that many high LogKOW non-pharmaceuticals fail to equilibrate in RED in protein-free controls, and thus had apparent values of Fub?=?0 in plasma. In these cases, Solid Phase Microextraction (SPME) as an alternative method provided an accurate, though more time-consuming, alternative to accurately determine Fub. We propose an updated IVIVE workflow that adds a protein-free control to the RED protocol, with the use of alternative approaches, such as SPME, in cases where compounds fail to adequately equilibrate. These refinements will provide additional confidence in the use of IVIVE as part of high-throughput screening programs of chemicals.

SUBMITTER: Ferguson KC

PROVIDER: S-EPMC6717004 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Comparative analysis of Rapid Equilibrium Dialysis (RED) and solid phase micro-extraction (SPME) methods for In Vitro-In Vivo extrapolation of environmental chemicals.

Ferguson Kyle C KC Luo Yu-Syuan YS Rusyn Ivan I Chiu Weihsueh A WA

Toxicology in vitro : an international journal published in association with BIBRA 20190610

In vitro to in vivo extrapolation (IVIVE) is a critical component of the efforts to prioritize and assess environmental chemicals using high-throughput in vitro assays. The plasma unbound fraction (F<sub>ub</sub>) is a key toxicokinetic parameter in IVIVE, and is usually measured via the Rapid Equilibrium Dialysis (RED) assay widely used for pharmaceuticals. However, pharmaceuticals have a narrower range of physicochemical properties than environmental chemicals. Motivated by the observation tha ...[more]

PMID: 31195086

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Project description: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.

Dataset Information

Comparative analysis of Rapid Equilibrium Dialysis (RED) and solid phase micro-extraction (SPME) methods for In Vitro-In Vivo extrapolation of environmental chemicals.

Publications

Comparative analysis of Rapid Equilibrium Dialysis (RED) and solid phase micro-extraction (SPME) methods for In Vitro-In Vivo extrapolation of environmental chemicals.

Similar Datasets

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