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Human gastrointestinal drug delivery; an experimental chimeric approach
1Department of Cellular Physiology, Babraham Institute, Cambridge, UK.
Abstract:
Studies of human gastrointestinal drug delivery are severely restricted by the complex ethical considerations which preclude many such investigations. In an attempt to overcome such restrictions we have utilised a chimeric mouse model, which is suitable for studying human gastrointestinal drug delivery under carefully defined experimental conditions. By means of subcutaneous transplantation of human intestine into scid mice, this host strain is able to accept and accommodate the xenografts for several months. Under these conditions, immature human fetal intestine differentiates onto a morphologically and functionally developed tissue which closely resembles normal human gut. The present work describes the use of this experimental system to study epithelial transcytosis of horseradish peroxidase, a model peptide, across human small intestine in vivo. The great potential for this model is that it lends itself to studies which are not feasible or unethical in patients and volunteers and, as such, provides a novel alternative means for gaining essential basic scientific information which is directly relevant to humans. This is especially important since experimental extrapolations made between species are often difficult, if not misleading.
Insights
This study introduces a chimeric mouse model for human gastrointestinal drug delivery research. This model enables in vivo studies of human intestinal drug absorption, overcoming ethical limitations in human trials.
Area of Science:
- Pharmacology
- Gastroenterology
- Biomedical Engineering
Background:
- Human gastrointestinal drug delivery studies face ethical restrictions, limiting research.
- Developing alternative models is crucial for advancing drug delivery science.
Purpose of the Study:
- To establish and validate a chimeric mouse model for studying human gastrointestinal drug delivery.
- To investigate epithelial transcytosis of a model peptide across human small intestine in vivo using this model.
Main Methods:
- Subcutaneous transplantation of human intestine into severe combined immunodeficient (SCID) mice.
- Cultivation of human fetal intestine xenografts to achieve mature, functional tissue.
- In vivo assessment of horseradish peroxidase (HRP) transcytosis across the human intestinal epithelium.
Main Results:
- The chimeric mouse model successfully supported the differentiation of human fetal intestine into functional tissue resembling normal human gut.
- The model allowed for in vivo study of epithelial transcytosis of horseradish peroxidase, a model peptide.
Conclusions:
- The chimeric mouse model offers a viable and ethical alternative for studying human gastrointestinal drug delivery.
- This model provides essential basic scientific information relevant to human drug absorption and transport, overcoming interspecies extrapolation challenges.