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In Vitro Characterization of Oral Absorption of Non-Pharmaceutical Chemicals
Citation:
Honda, G., C. Strock, D. Angus, R. Dinallo, R. Pearce, R. Thomas, AND J. Wambaugh. In Vitro Characterization of Oral Absorption of Non-Pharmaceutical Chemicals. Presented at Society of Toxicology Annual Meeting, San Antonio, Texas, March 11 - 15, 2018. https://doi.org/10.23645/epacomptox.6863801
Impact/Purpose:
This presentation describes new experiments attempting to use in vitro methods to characterize oral absorption of environmentally-relevant chemicals. These data should reduce uncertainty associated with the use of the HTTK tool developed by the CSS RED project.
Description:
The toxicokinetic extrapolation of in vitro exposure to in vivo doses may be improved by using data for fraction absorbed (Fa) through the intestine, but these data are not commonly available for non-pharmaceutical compounds. Caco-2 cells, developed from human colon carcinoma cells, form a polarized monolayer that behaves similarly to the human intestinal epithelium. Permeability rates in the Caco-2 assay are highly correlated with Fa (Artursson et al.). In this work, permeability was measured in vitro using a Caco-2 assay for 404 ToxCast chemicals. Transport was assessed from apical to basolateral (Papp,AB) and 353 chemicals had detectable values of Papp,AB. Fa in humans was estimated from Papp,AB using a previously published model (Darwich et al.). For orally dosed pharmaceuticals, it is typically expected that Fa is near 1. In this work, 80% of the 353 ToxCast chemicals had predicted Fa ≥ 0.90, while the median Fa for the other chemicals was 0.57. While assuming Fa = 1 may be a reasonable estimate, there are many cases where Fa was predicted to be significantly lower. The predicted Fa from the Darwich model, as well as predicted Fa from the model by Usansky and Sinko (requiring volume of distribution), were compared with literature values for Fa in human for 20 chemicals, and results were highly correlated (MSE of 0.01 and 0.06). Predicted Fa was then used to estimate the fraction of oral bioavailability (Fbio) by incorporating previously measured values for intrinsic hepatic clearance (Clint) to determine the first pass hepatic clearance (FFP¬). Assuming similarity for Fa between rats and humans, calculated values for Fbio from the Darwich and Usansky models were strongly correlated when compared with in vivo measured values in the rat (MSE of 0.12 and 0.07, respectively) for 14 chemicals. Predicted Fbio were also determined using in silico values for Fa from GastroPlus coupled with FFP determined from in vitro measured Clint. GastroPlus predictions were correlated with in vivo measured values in the rat (MSE of 0.11), suggesting the potential of using in silico methods to predict Fa. This abstract does not necessarily reflect U.S. EPA policy. Artursson et al. Adv. Drug Deliv. Rev. 2001, 46, 27-43. Darwich et al. Current Drug Metabolism, 2010, 11, 716-729. Usansky, H.; Sinko, P. J. Pharm. Exp. Ther., 2005, 314, 391-399.
URLs/Downloads:
DOI: In Vitro Characterization of Oral Absorption of Non-Pharmaceutical Chemicals
HONDA_CACO2_SOT2018_28FEB2018.PDF (PDF, NA pp, 841.959 KB, about PDF)