Epithelial and microbial determinants of colonic drug distribution.

A dynamic epithelium and a rich microbiota, separated by multi-layered mucus, make up the complex colonic cellular environment. Both cellular systems are characterized by high inter- and intraindividual differences, but their impact on drug distribution and efficacy remains incompletely understood. This research gap is pressing, as, e.g., inflammatory disorders of the colon are on the rise globally. In an effort to help close this gap, we provide considerations on determining colonic epithelial and microbial cellular parameters, and their impact on drug bioavailability. First, we cover the major cell types found in vivo within the epithelium and microbiota, and discuss how they can be modeled in vitro. We then draw attention to their structural similarities and differences with regard to determinants of drug distribution. Once a drug is solubilized in the luminal fluids, there are two main classes of such determinants: 1) binding processes, and 2) transporters and drug-metabolizing enzymes. Binding lowers the unbound intracellular fraction (f

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