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Title: NMR-based metabonomics of pre-clinical models of isoniazid and gentamicin toxicity
Author: Cunningham, Katharine
ISNI:       0000 0004 2736 8737
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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An individual's response to drug therapy is the result of complex interactions between environmental and genetic factors. The ability to characterise inter-individual variation in response to pharmaceutical intervention is of particular importance in a clinical setting, where variation in response can result in therapeutic failure or adverse effects in individuals or sub-populations of patients. Given the success of NMR-based techniques for metabolic profiling, this thesis focused on characterisation of the systems-wide endogenous metabolic response to isoniazid and gentamicin. Throughout this work, one-dimensional 1H and two-dimensional 1H NMR of biofluids and tissue was applied to generate metabolic profiles reflective of response to pharmaceutical intervention in the animal model, in conjunction with conventional clinical chemistry and histopathological assessment. Isoniazid is a widely prescribed anti-tubercular treatment that has toxic side effects: it is widely associated with both hepatotoxicity and peripheral neurotoxicity in the clinical setting. Here, a relationship was established between the post dose profile of drug metabolites and the severity of the adverse effect on the central nervous system. Further, the metabonomic approach resulted in the identification of pre-dose urinary markers of toxic outcome. The aminoglycoside antibiotic gentamicin is a known nephrotoxin. Clinical chemistry and histopathology identified clear differences in the degree of nephrotoxicity experienced by the rat relative to administration time. Complementary metabolic profiling techniques were then applied to the analysis of urine and kidney tissue, and identified clear metabolic differences in response to treatment time. A final study then explored whether co-administration of a statin (atorvastatin) could reduce gentamicin-induced nephrotoxicity in the rat. Conventional toxicity assessments indicated that co-administration of gentamicin and atorvastatin was non-toxic, while metabonomic analysis of urine and kidney tissue indicated that there were metabolic differences, likely linked to the antibiotic effect of gentamicin. This work highlights the potential for beneficial drug-drug interactions to decrease a drugs toxic effect, as well as the importance of considering administration time when developing treatment regimens.
Supervisor: Nicholson, Jeremy ; Coen, Muireann ; Holmes, Elaine Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral