Model-based Exploration of Chemical Absorption and Metabolism Kinetics in the Human Gastrointestinal Tract

Evaluating the oral bioavailability (Fbio) of ingested chemicals in the human gastrointestinal tract is pivotal for assessing chemical concentrations in the human systemic circulation and informing potential toxicological impacts, especially in the era of "new approach methods" targeting chemical screening and prioritization. This dissertation advances the understanding and predictions of chemicals' Fbio from the perspectives of chemical properties and mass-balance modeling. First, the rate at which a chemical can transport across membranes is an important indicator of how fast it can be absorbed by humans. Therefore, the possibility and challenge of adapting one of the popular transmembrane permeability models in the pharmaceutical industry, parallel artificial membrane permeability assay (PAMPA), for use with chemicals of environmental concern (CEC) is explored. The results underscore the importance of considering chemical properties when applying the current design of PAMPA to chemicals of environmental concern due to the differences in the physiochemical properties between CECs and pharmaceuticals. In addition, pre-absorption metabolism can potentially play an important role in the Fbio of CECs. Therefore, a physiological-based toxicokinetic (PBTK) model is built to understand the potential of chemicals to undergo pre-systemic metabolism, especially in the human gut lumen. The results show that gut lumen metabolism can significantly reduce the Fbio of CECs, for instance, by more than 80% for di(2-ethylhexyl)phthalate. Therefore, when assessing the Fbio of CECs, it is crucial to consider gut lumen metabolism. Additionally, the results show that the gut absorption rate (kabs) or fraction absorbed in the gut (Fabs) can be an important factor not only affecting Fbio by controlling the rate of absorption but also affecting gut lumen metabolism. Therefore, I built a model to understand Fabs from the perspectives of both transmembrane permeability and partition coefficients. The results show that permeability and partition coefficients interactively control Fabs. Consequently, when assessing the Fabs of CECs, both chemical properties must be considered.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

Doctorate Degree

Year dc:date.issued

2024

Author dc:creator

• Wang, Shenghong

Advisor dc:contributor.advisor

• Li, Li

Committee members dc:contributor.committeemember

• Khlystov, Andrey
• Li, Dingsheng
• Ryu, So Young
• Yang, Wei

Language dc:language.iso

en_US, English

Repository record dc:identifier.uri

https://scholarwolf.unr.edu/handle/11714/11157

OAI identifier oai:identifier

oai:scholarwolf.unr.edu:11714/11157