Evaluatie van de dikke darmomgeving en de implicaties voor het gedrag van geneesmiddelen

Studies on oral drug performance typically focus on the upper small intestine, as this is the first major absorptive site a drug encounters. However, for optimal delivery and activity of drugs to/in the colon, it is crucial to thoroughly understand the colonic environment and how it affects drug and formulation behaviour. High permeability and lack of degradation by the microbiome are pre-requisites for efficient drug absorption in the colon. However, development of colon-targeting formulations for poorly soluble compounds (BCSII) has shown to be challenging due to a lack of clinically useful drug absorption data and poor predictions of colonic absorption despite high in vitro permeability and stability. It is hypothesized that there are limitations to successful colonic drug delivery and absorption beyond standard dose, solubility and permeability considerations. Such aspects include interactions with uptake and efflux transporters, binding to luminal components, slow diffusion, mucus barrier effects, and metabolism by phase I and phase II enzymes in the enterocytes or by colonic microbiota. In this project, various aspects will be investigated to increase our understanding of drug and formulation behaviour in the colon, including the assessment of transporters and enzymes in the colonic mucosa from healthy volunteers and colorectal cancer patients and their impact on drug disposition.