Thesis
Mapping natural variability in human intestinal fluid to simulated media : implications for Caco-2 permeability studies
- Creator
- Rights statement
- Awarding institution
- University of Strathclyde
- Date of award
- 2026
- Thesis identifier
- T18189
- Person Identifier (Local)
- 202281413
- Qualification Level
- Qualification Name
- Department, School or Faculty
- Abstract
- Biopharmaceutics is the study of how the physical and chemical properties of a drug influence its absorption, distribution, metabolism and excretion (ADME) within the human body, with the aim of optimising the drug development pipeline so that therapeutic benefit is maximised, and adverse effects minimised. Central to this is the accurate prediction of oral absorption, which depends on reliable measurements of both solubility and permeability. While considerable progress has been made in generating biorelevant solubility data, permeability is still routinely assessed in simple buffer systems that bear little resemblance to the colloidal environment of the small intestine. As a consequence, the permeability values used as inputs into predictive software may not reflect the conditions drugs encounter in vivo. This thesis addresses that gap by applying a suite of simulated intestinal fluids (SIF), developed through statistical evaluation of human intestinal fluid composition, to the Caco2 model, with the aim of generating more physiologically representative permeability data. Four objectives were pursued. Chapter 2 investigates the development of a single gas chromatography-mass spectrometry method capable of quantifying the components of these media alongside the drug within the same sample. Chapter 3 examines the capacity of Caco-2 monolayers to withstand the stress imposed by compositionally complex media, identifying which formulations are compatible with the model and can be carried forward. Chapter 4 applies the selected media to the Caco-2 Transwell™ system, determining the apparent permeability of drugs spanning different classes of the Biopharmaceutics Classification System (BCS) and examining the variability that arises when a simple buffer is replaced by a colloidal medium. Chapter 5 turns to variability within the model itself, using absolute protein quantification by QconCat analysis to characterise how transporter and enzyme expression changes with passage number, thereby defining the passage range appropriate for experimental use, and comparing these profiles with paediatric biopsy data to assess the suitability of the model for predicting absorption in paediatric populations. Together, this work expands the limited data available on drug permeability in simulated intestinal fluids and provides both a method and a mechanistic basis for assessing drug performance under physiologically realistic gastrointestinal conditions.
- Advisor / supervisor
- Batchelor, Hannah
- Resource Type
- DOI
- Funder
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PDF of thesis T18189 | 2026-10-07 | Public | Download |