The broad objective of this proposal is to exploit the large and varied analytical capability of mass spectrometry in the solution of challenging problems in pharmacology. The specific problems we wish to address include the synthesis and characterization of glucuronides, pharmacokinetics and mode of action of chemotherapeutic alkylating agents and the development of new reagent ions for charge exchange ionization. In the glucuronide area we propose to develop procedures for the synthesis of glucuronides using UDP-glucuronyl transferase which have immobilized on beaded sepharose, to develop and apply a gas chromatography-mass spectrometric assay for prostatic androgen glucuronides using deuterium-labelled internal standards, and to synthesize and characterize glucuronides for reference and testing of a variety of thioxanthenes, cannabinols, sterols, alkaloids, and polyfunctional aglycons. In addressing the pharmacology of alkylating agents we propose to develop a gas chromatography-mass spectrometric assay technique for phenylalanine mustard and two metabolites, to apply this assay in clinical studies, to study the mechanism of alkylation of phenylalanine mustard, and to isolate and characterize the products of reactions of chemotherapeutic alkylating agents with deoxyguanosine.
NIH ExPorter
NIH ExPorter