Development of physiologically based gut absorption model for probabilistic prediction of environmental chemical bioavailability
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Abstract
Absorption in the gastrointestinal tract is a key factor determining the bioavailability of chemicals after oral exposure but is frequently assumed to have a conservative value of 100% for environmental chemicals, particularly in the context of high-throughput toxicokinetics for in vitro-to-in vivo extrapolation (IVIVE). For pharmaceutical compounds, the physiologically based advanced compartmental absorption and transit (ACAT) model has been used extensively to predict gut absorption but has not generally been applied to environmental chemicals. Here we develop a probabilistic environmental compartmental absorption and transit (PECAT) model, adapting the ACAT model to environmental chemicals. We calibrated the model parameters to human in vivo, ex vivo, and in vitro datasets of drug permeability and fractional absorption by considering two key factors: (1) differences between permeability in Caco-2 cells and in vivo permeability in the jejunum, and (2) differences in in vivo permeability across different gut segments. Incorporating these factors probabilistically, we found that given Caco-2 permeability measurements, predictions of the PECAT model are consistent with the (limited) available gut absorption data for environmental chemicals. However, the substantial chemical-to-chemical variability observed in the calibration data often led to wide probabilistic confidence bounds in the predicted fraction absorbed and resulting steady state blood concentration. Thus, while the PECAT model provides a statistically rigorous, physiologically based approach for incorporating in vitro data on gut absorption into toxicokinetic modeling and IVIVE, it also highlights the need for more accurate in vitro models and data for measuring gut segment-specific in vivo permeability of environmental chemicals.
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