The majority of intestinal in vitro screening models use cell lines that do not reflect the complexity of the human intestinal tract and hence often fail to accurately predict intestinal...
Over the past few years, atomic force microscopy (AFM) has developed as a mature research tool for measuring the nanomechanical properties of tissue, cells and biological structures. The force spectroscopy mode of AFM allows the local elasticity of biological samples to be measured. The mechanical properties of cells are highly affected by homeostatic changes observed during disease. In the case of the intestine, the aetiology for some conditions is still unclear. To improve the clinical translation of pre-clinical models, a new and different approach could be to study cellular behaviour in health and disease from a mechanical point of view. Specifically, knowledge of changes in epithelial membranes in response to drugs is useful for interpreting both drug action and disease development. Here, we used human intestinal Caco-2 cells as a first step to record epithelial membrane elasticity measurements at the nanoscale using AFM. Three different drugs were selected to influence intestinal epithelium integrity by specifically targeting different functional aspects of the membrane, such as permeability and support. Results indicate a relationship between measured cell elasticity and cell viability markers, such as cellular toxicity and membrane barrier functions. Our work represents a proof-of-concept that cells suffer a particular change in elastic properties depending upon the mechanism of action of an applied drug. The following may provide an efficient approach for diagnosing intestinal pathologies and testing drugs for clinical use.
STATEMENT OF SIGNIFICANCEWe present evidence that epithelial membrane suffers a particular change in elastic properties depending upon the mechanism of action of an applied drug. These changes can be monitored over time using AFM technology and may provide an alternative and efficient approach for diagnosing intestinal pathologies and testing drugs for clinical use.
To predict the absorption, distribution, metabolism and excretion (ADME) profile of candidate drugs a variety of preclinical models can be applied. The ADME and toxicological behavior of newly developed drugs are often investigated prior to assessment in humans, which is associated with long time-lines and high costs. Therefore, good predictions of ADME profiles earlier in the drug development process are very valuable. Good prediction of intestinal absorption and renal and biliary excretion remain especially difficult, as there is an interplay of active transport and metabolism involved. To study these processes, including enterohepatic circulation, ex vivo tissue models are highly relevant and can be regarded as the bridge between in vitro and in vivo models. In this review the current in vitro, in vivo and in more detail ex vivo models for studying pharmacokinetics in health and disease are discussed. Additionally, we propose novel models, i.e., perfused whole-organs, which we envision will generate valuable pharmacokinetic information in the future due to improved translation to the in vivo situation. These machine-perfused organ models will be particularly interesting in combination with biomarkers for assessing the functionality of transporter and CYP450 proteins.
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