Publication: Experimental Validation of Mass Balance Models for in Vitro Cell-Based Bioassays

The freely dissolved concentration in the assay medium (Cfree) and the total cellular concentration (Ccell) are essential input parameters for quantitative in vitro-to-in vivo extrapolation (QIVIVE) studies, but available prediction tools for Cfree and Ccell have not sufficiently been validated with experimental data. In this study, medium-water distribution ratios (DFBS/w) and cell-water distribution ratios (Dcell/w) for four different cells lines were determined experimentally for 12 neutral and five ionizable chemicals. Already published data for seven organic acids were added to the dataset. A mass balance model based on bovine serum albumin-water (DBSA/w) and liposome water distribution ratios (Dlip/w) of the chemicals was used to calculate DFBS/w and Dcell/w. For all neutral and basic test chemicals, the mass balance model predicted DFBS/w and Dcell/w within a factor of 3 and 3.4, respectively, indicating that existing models can reliably predict Cfree and Ccell for these chemicals. For organic acids a further refinement of the model will be required as large deviations between modelled and measured binding to assay medium and cells of up to a factor of 370 were found. Furthermore, saturation of medium proteins should be further explored for organic acids and neutral chemicals with moderate hydrophobicity.

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