THE ANALYTICAL CHEMISTRY OF ANTI-AIDS AGENTS

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The objective of this project is the research and development of suitable bioanalytical methods to: (1) establish the structure and purity of potential anti-AIDS agents and new antiviral drugs, (2) determine the physical, chemical and biochemical properties, including octanol-water partition coefficients, of these compounds and their metabolites, and (3) measure these drugs and their metabolites in biological samples to elucidate pharmacology and to determine pharmacokinetics. High-performance liquid chromatography (HPLC) and mass spectrometry are the emphasized techniques. The Phase I drug 2'-beta-fluoro-2',3'-dideoxyadenosine (F-ddA) and its deaminated anti-HIV-active metabolite 2'-beta-fluoro-2',3'-dideoxyinosine (F-ddI) remain the compounds of primary interest. Analytical strategies employing reversed-phase HPLC have been developed and validated for both the routine and ultrasensitive measurement of F-ddA in HIV-infected human biological fluids. Fluorogenic derivatization and HPLC analysis with fluorescence detection allow measurement of F-ddA at nanomolar levels in plasma. The metabolism, distribution and pharmacokinetics of F-ddA is under investigation following intravenous and oral administration during a Phase I clinical trial of this agent in AIDS patients. Preliminary results indicate that the bioavailability of oral F-ddA is good (>50%). Lipophilic prodrugs of F-ddI activated by adenosine deaminase also continue under investigation. HPLC methodology for the measurement of 6-chloro-2',3'-dideoxypurineriboside in biological fluids and tissues has been developed and applied to show enhancement of central nervous system penetration of F-ddI in rats after administration of this prodrug. Direct fluorogenic derivatization of cellular extracts in conjunction with paired-ion HPLC has been employed for the nonradiochemical measurement of subpicomole amounts of intracellular F-ddATP, the active metabolite of both F-ddA and F-ddI.