THE ANALYTICAL CHEMISTRY OF ANTI-AIDS AGENTS

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The objective of this project is the research and development of suitable analytical methods to: (1) establish the structure and purity of potential anti-AIDS agents and new antiviral drugs, (2) determine 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-perfor- mance liquid chromatography and mass spectrometry are emphasized techniques. Sugar-fluorinated dideoxynucleosides, including 2'-F-dd-ara-A, 2'-F-dd-ara-I, and 6-substituted-2'-F-dd-Purines, are currently the compounds of primary interest. An HPLC method for measuring both 2'-F-ara-ddA and 2'-F-dd-ara-I in plasma, urine and cerebrospinal fluid has been developed, validated and applied to determine plasma and CSF pharmacokinetics in monkeys and rats. 2'-F-ara-ddA exhibits enhanced central nervous system penetration with respect to its inosine analogue in both species. The role of adenosine deaminase in prodrug activation is under investigation.