title: Including carrier-mediated transport in oral uptake prediction of nutrients and pharmaceuticals in humans.
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.
authors.affiliation: 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.
authors.forename: Isabel A
authors.initials: IA
authors.lastname: O'Connor
authors.affiliation: Radboud University Nijmegen, Institute for Water and Wetland Research, Department of Environmental Science, PO Box 9010, NL-6500 GL Nijmegen, The Netherlands.
authors.forename: Karin
authors.initials: K
authors.lastname: Veltman
authors.affiliation: Radboud University Nijmegen, Institute for Water and Wetland Research, Department of Environmental Science, PO Box 9010, NL-6500 GL Nijmegen, The Netherlands.
authors.forename: Mark A J
authors.initials: MA
authors.lastname: Huijbregts
authors.affiliation: 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.
authors.forename: Ad M J
authors.initials: AM
authors.lastname: Ragas
authors.affiliation: 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.
authors.forename: Frans G M
authors.initials: FG
authors.lastname: Russel
authors.affiliation: Radboud University Nijmegen, Institute for Water and Wetland Research, Department of Environmental Science, PO Box 9010, NL-6500 GL Nijmegen, The Netherlands.
authors.forename: A Jan
authors.initials: AJ
authors.lastname: Hendriks
mesh_terms: D000284:Administration, Oral; D001692:Biological Transport; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions / Q000187:drug effects; D008954:Models, Biological; D015262:Xenobiotics / Q000008:administration & dosage* / Q000493:pharmacokinetics*
chemical_list: D015262:Xenobiotics
keywords: Carrier-mediated; In vitro; In vivo; Model; Oral uptake; Passive diffusion