APPLICATIONS OF NEW MASS SPECTRAL TECHNIQUES

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The objective of this project is development of new mass spectral techniques in order to provide innovative and/or more rapid solutions to problems involving (1) chemical structure determination, (2) complex mixture analysis and (3) measurement of trace components in biological systems. Electrospray ionization mass spectrometry (ESI/MS), tandem mass spectrometry (MS/MS) and combined liquid chromatography-mass spectrometry (LC/MS) are the techniques of current interest. A narrow-bore (2 mm i.d., 0.200 ml/min), reversed-phase liquid chromatography system, whose flow can be automatically diverted for sample desalting, has been developed for general ESI/MS analysis of biological samples. This LC/ESI/MS system has been used to develop a rapid method utilizing tandem mass spectrometry for measuring the Phase I anti-AIDS drug 2'-beta-fluoro-2',3'-dideoxyadenosine (F-ddA) and its anti-HIV-active deaminated metabolite 2'-beta-fluoro-2',3'-dideoxyinosine (F-ddI) in human plasma with high specificity and sensitivity. This methodology is being applied to determine the pharmacokinetics and bioavailability of oral F-ddA during the initial Phase I clinical trial of this agent in AIDS patients. Fast atom bombardment mass spectrometry (FAB/MS) is used to support the LMC synthetic effort through structural characterization of new compounds and synthetic intermediates. FAB liquid matrix reactions involving ion pairing, reduction, dehalogenation and radical cation/anion formation continue to be studied and characterized to ensure the interpretability and reliability of these analyses.