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Title: Applications of liquid chromatography/mass spectrometry in studies of drug metabolism
Author: Maltas, J.
Awarding Body: University College of Swansea
Current Institution: Swansea University
Date of Award: 1993
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The studies described in this thesis have explored the scope and limitations of using thermospray LC-MS as a routine analytical technique for providing the quantitative and qualitative data necessary to support the drug development process. Repeller assisted discharge ionisation, also known as plasmaspray, has also been investigated as an adjunct to thermospray for structural analysis of both Phase 1 and Phase 2 drug metabolites. There are four main subject areas encompassed by these studies namely drug metabolism, pharmacokinetics, high performance liquid chromatography and combined high performance liquid chromatography-mass spectrometry. Optimisation of the numerous system parameters is a prerequisite for all analyses and the extent to which the mobile phase composition, vaporiser temperature and repeller voltage affect the sensitivity of detection has been investigated using model compounds. The absolute responses obtained were compound dependent but all of the compounds tested demonstrated best sensitivity when the proportion of methanol in the mobile phase was high, generally greater than 60%. The repeller voltage was also found to have considerable influence on the intensity of response for all compounds, whilst the concentration of ammonium acetate in the mobile phase and the vaporiser temperature were less critical. These findings have led to the adoption of a modified approach to LC-MS in which the chromatography is performed at reduced flow rates, typically 0.5 ml min-1, and the column effluent is then enriched with methanol containing ammonium acetate to give a total flow compatible with optimum performance of the thermospray interface. This procedure has been found to be suitable for quantitative and qualitative analyses. The adoption of post-column addition of methanol has enabled the use of lower operating temperatures on the thermospray interface which has in turn led to a reduction in the extent to which labile compounds undergo thermal decomposition. This has proven to be a simple yet successful approach, illustrated by the identification of two unusual conjugates, a sulphamate and a carbamoyl-glucuronide, of GR50360 and a glutathione conjugate of GR55721. The analysis of these metabolites had proven problematic prior to the use of the post-column addition of methanol.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available