The pharmacokinetic response of a drug, following oral administration, relies on the environment within the gut, which is dynamic and responds spontaneously to the stimuli from ingesta. The models used in drug development must encompass the comprehensive knowledge of the gut, which is merely considered a digestive organ, but in reality, is a very complex environment. The work, presented in this thesis, focuses on both the in-vitro and in-vivo models used in drug delivery research, and links the importance of the data from in-vitro and in-vivo studies to in-silico predictions of pharmacokinetic behaviour. We have proposed two in-vitro media, each simulating the conditions of the proximal and the distal human small intestine by exploiting physiological bicarbonate buffer, which is the principal buffer system of the body and also of the gastrointestinal milieu. Our studies with enteric coated products, designed for small intestinal and ileocolonic delivery, have shown that the use of bicarbonate buffer provides improved predictions, compared to compendial phosphate buffers. The proposed physiological bicarbonate system was also used to study metal-ion interactions with enteric polymers, such as polymethacrylates. It was shown that the metal ions formed complexes with polymethacrylates rendering the coat insoluble in the gastrointestinal conditions. The compendial phosphate media failed to probe such interactions due to in-situ precipitation of the metal phosphates, which obliterated the buffer species from the media. The in-vitro drug release from various enteric-polymer coated prednisolone tablets studied in physiological buffer was then used in in-silico tools (Gastrol'lus" and SimCyp®), and it provided more realistic, discriminatory and variable response, usually anticipated from the clinical knowledge. The in-silico tools were also exploited to simulate the influence of gender differences in gastrointestinal physiology on pharmacokinetics. Our studies with animal models highlighted significant inter-species differences in the anatomy and physiology of the gut in rat, guinea pig, rabbit and pig, which could lead to unrealistic expectations when these animal models are used in pre-clinical studies. Moreover, our studies with rats suggested that ageing affects the features of the gastrointestinal tract, which may have implications for drug delivery to young, adult and elderly subjects.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:550963 |
| Date | January 2012 |
| Creators | Ali Merchant, Hamid |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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