Novel methods for the quantitation of central nervous system agents
Williamson, Leah Nicole
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Humans can be exposed to central nervous system agents environmentally and/or therapeutically. Chronic exposure to these agents can cause damage to the central nervous system. In order to study the neurological effects of these agents, sensitive and selective analytical methods must be developed and validated in biological matrices, such as brain tissue, plasma, and whole blood. Chlorpyrifos (CPF) is an organophosphate pesticide that inhibits acetylcholinesterase, which is an enzyme that is necessary for normal function of the nervous system. CPF is metabolized by cytochrome P450 into chlorpyrifos-oxon (CPF-O) and TCP. CPF-O is about 3,000 times more potent than CPF in its inhibition of acetylcholinesterase activity, while TCP is non-toxic and is eliminated by the kidneys. Therapeutically, chronic exposure to antipsychotic drugs can result in abnormalities in motor function. Additionally, it is important to determine the extent to which a correlation exists between plasma and brain levels of these agents and cognitive function. Chapter 1 is the introduction and literature review that describes the layout of the dissertation and reviews the literature for analytical methods using liquid chromatography with time-of-flight mass spectrometry (TOF-MS) for quantitation. Chapter 2 reviews the literature for analytical methods using gas chromatography and TOF-MS for quantitation. Chapters 3 and 4 present analytical methods for the quantitation of CPF and its metabolites in rat brain tissue and blood using liquid chromatography and tandem mass spectrometry (LC-MS/MS). A TOF-MS analytical method for the quantitation of five antipsychotic drugs in rat plasma is presented in chapter 5.