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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Biological Transport
  • Humans
  • Hydrophobic and Hydrophilic Interactions / drug effects
  • Models, Biological
  • Xenobiotics / administration & dosage*
  • Xenobiotics / pharmacokinetics*

Substances

  • Xenobiotics