Plasma, liver, and kidney exposures in rats after oral doses of industrial chemicals predicted using physiologically based pharmacokinetic models: A case study of perfluorooctane sulfonic acid

Abstract

A simplified physiologically based pharmacokinetic (PBPK) model consisting of chemical receptor, metabolizing and/or excreting, and central compartments was recently proposed. In the current study, this type of PBPK model was set up for perfluorooctane sulfonate, an environmental toxicant with liver effects, as a model compound; the model was then used to estimate tissue concentrations. The pharmacokinetic parameter input values for the model were calculated to give the best fit to reported/measured blood substrate concentrations in rats. The maximum concentrations and areas under the concentration versus time curves in plasma, liver, and kidney extrapolated using PBPK models for perfluorobutane sulfonic acid, perfluorohexane sulfonic acid, and perfluorooctane sulfonic acid were consistent with the reported mean values in rats. Using the rat models and scaled-up human PBPK models, some accumulation of perfluorooctane sulfonic acid in plasma and liver was seen after repeated doses. The reported 50th and 95th percentile concentrations of perfluorooctane sulfonic acid in human blood (0.0048 and 0.0183 ng/mL, respectively) in the general population underwent reverse dosimetry analysis using our PBPK models. These human blood concentrations potentially imply exposures of 0.041 and 0.16 µg/kg/day, respectively, for 90 days, values that are roughly similar to the reference dose (0.02 μg/kg/day) with an uncertainty factor of 30. These results indicate the relatively good estimates for tissue and blood exposures of chemical substrates after oral doses generated using the latest PBPK models.

Pharmacokinetics of primary oxidative metabolites of thalidomide in rats and in chimeric mice humanized with different human hepatocytes

“…A simplified rat PBPK model consisting of chemical receptor (gut), metabolizing (liver), excreting (kidney), and central compartments was set up as described elsewhere (Kamiya et al, 2020b(Kamiya et al, , 2021. The molecular weights (258, 274, and 274), octanol-water partition coefficients (clogP; 0.528, -0.138, and 0.402), plasma unbound fractions (f u,p ; 0.588, 0.615, and 0.237), and blood-plasma concentration ratios (R b ; 0.893, 0.885, and 0.904) of thalidomide, 5′-hydroxythalidomide, and 5-hydroxythalidomide, respectively, were used as described previously (Nishiyama et al, 2015;Yamazaki et al, 2012).…”

Metabolic profiles for the pyrrolizidine alkaloid neopetasitenine and its metabolite petasitenine in humans extrapolated from rat <i>in vivo</i> and <i>in vitro</i> data sets using a simplified physiologically based pharmacokinetic model

“…Simplified rat PBPK models for neopetasitenine and petasitenine composed of chemical receptor (gut), metabolizing (liver), excreting (kidney), and central compartments were established as described elsewhere (Kamiya et al, 2020c;Miura et al, 2021). The values used for the hepatic and renal blood flow rates (Q h and Q r ) in rats (0.853 L/hr) and humans (96.6 L/hr) and the hepatic and renal volumes (V h and V r ) in rats (8.5 and 3.7 mL) and humans (1.5 and 0.28 L), respectively, were described previously (Kamiya et al, 2020a).…”