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Environ Toxicol Pharmacol. 2014 Nov;38(3):938-47. doi: 10.1016/j.etap.2014.10.007. Epub 2014 Oct 22.

Including carrier-mediated transport in oral uptake prediction of nutrients and pharmaceuticals in humans.

Author information

1
Radboud University Nijmegen, Institute for Water and Wetland Research, Department of Environmental Science, PO Box 9010, NL-6500 GL Nijmegen, The Netherlands. Electronic address: i.oconnor@science.ru.nl.
2
Radboud University Nijmegen, Institute for Water and Wetland Research, Department of Environmental Science, PO Box 9010, NL-6500 GL Nijmegen, The Netherlands.
3
Radboud University Nijmegen, Institute for Water and Wetland Research, Department of Environmental Science, PO Box 9010, NL-6500 GL Nijmegen, The Netherlands; Open University, School of Science, PO Box 2960, NL-6401 DL Heerlen, The Netherlands.
4
Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Department of Pharmacology and Toxicology (149), PO Box 9101, NL-6500 HB Nijmegen, The Netherlands.

Abstract

Most toxicokinetic models consider passive diffusion as the only mechanism when modeling the oral uptake of chemicals. However, the overall uptake of nutrients and xenobiotics, such as pharmaceuticals and environmental pollutants, can be increased by influx transport proteins. We incorporated carrier-mediated transport into a one-compartment toxicokinetic model originally developed for passive diffusion only. The predictions were compared with measured oral uptake efficiencies of nutrients and pharmaceuticals, i.e. the fraction of the chemical reaching systemic circulation. Including carrier-mediated uptake improved model predictions for hydrophilic nutrients (RMSE=10% vs. 56%, Coefficient of Efficiency CoE=0.5 vs. -9.6) and for pharmaceuticals (RMSE=21% vs. 28% and CoE=-0.4 vs. -1.1). However, the negative CoE for pharmaceuticals indicates that further improvements are needed. Most important in this respect is a more accurate estimation of vMAX and KM as well as the determination of the amount of expressed and functional transport proteins both in vivo and in vitro.

KEYWORDS:

Carrier-mediated; In vitro; In vivo; Model; Oral uptake; Passive diffusion

PMID:
25461554
DOI:
10.1016/j.etap.2014.10.007
[Indexed for MEDLINE]

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