de Sousa, Tiago José Teixeira Bernardo; (2009) An assessment of the role of stability on the behaviour of drugs in the colonic environment. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

There are 100 trillion (10^14) microbes in the human gastrointestinal tract, concentrated mainly in the large intestine. They secrete a diverse array of enzymes giving them an immense metabolic potential, which has serious implications for drugs exposed to the large intestinal environment. The aim of this thesis was to investigate in vitro and in vivo factors that impact on the metabolic stability of a series of compounds. Analytical HPLC-UV methodologies were developed to quantify the model drugs sulfasalazine, balsalazide, olsalazine, 5-aminosalicylic acid, sulindac and metronidazole from a bacterially rich faecal environment. LC/MS methodologies were developed for the sensitive analysis of the model drugs from plasma. A new and simple LC/MS method for the plasma analysis of captopril was also developed. An easy and ready-to-use in vitro model fermenter to routinely test drug molecules for bacteria-related stability, using human faecal slurry, was developed and validated. Similarity was observed between model drugs metabolic rates using faecal slurry collected from different volunteers. The slurry concentration affects drug degradation and 10%w/v seems to combine easier handling/accurate volume measurement with good metabolic activity. The use of smaller volumes (<lml) and independent vials (as opposed to 96 well plates) reduces the variability of drug degradation rates. The presence of nutrients increases in vitro drug metabolism. In this in vitro model, drug stability in rat intestinal contents and dog faecal material was also assessed, the contents of these animals in vitro predict drug metabolic trends obtained with human faecal slurries for the model drugs studied. For the first time a fistulated dog model was used to study bacteria-related drug metabolism in vivo and successfully detected the appearance of the bacterial drug metabolites in plasma. Furthermore the use of antibiotics for the study of bacteria-related drug metabolism was assessed in vivo and further work is required to fully assess the use of antibiotics to assess bacteria-related drug stability in vivo. Given the potentially serious implications of bacterial metabolism on drug performance or toxicity, an assessment of the action of the microbiota should form an integral part of the drug development process. Therefore the model developed in this thesis will be of primary value to scientists working in early drug development where new drug molecules/formulations are being developed that reach the lower confines of the gastrointestinal tract.

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