Physiologically Based Pharmacokinetic (PBPK) Modeling Approaches for Studying Oral Absorption of Volatile Compounds Based on Rates of Exhalation. M. B. Reddy and M. E. Andersen, Colorado State University
Reference Concentrations (RfC) account for differences in tissue dose between animals and humans. References Dose (RfD) calculations do not. This is partly due to deficiencies in understanding factors that regulate oral absorption from the gastrointestinal (GI) tract. With volatile compounds, time-dependencies of GI-absorption can be inferred from elimination in exhaled air after oral dosing. This non-invasive design could be applied to laboratory animals or to humans. We have developed several PBPK models to assess oral absorption. This paper describes simple PBPK models with a GI tract, liver, body, fat, lung, and flow through measuring chamber. Chemical uptake into portal blood was first-order with saturable hepatic metabolism. We evaluated effects of dose rate (i.e., vehicle), hepatic clearance, blood:air and tissue:blood partition coefficients, and chamber characteristics to see how exhalation data may be used to understand the oral absorption of these compounds. The best sensitivity arises from direct measurements of exhaled breath rather than through a sampling chamber with selected model parameters. A second absorption scenario evaluated was pulsatile input, with evaluation of the chemical characteristics that allow pulsatility to appear in the exhalation curves. Pulses were best characterized with small Pb:a. As Pb:a increased, pulse behavior was smoothed out by the storage capacity of blood and tissues. Pulses were also damped by metabolism and by high flow or volume in the sampling chamber. For exhalation studies, judicious choice of test chemicals, on the basis of partitioning and metabolism characteristics, could provide data for improving interspecies extrapolation of absorption rates and tissue dose for orally administered compounds.
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