APPLICATIONS OF MASS SPECTROMETRY IN PHARMACOLOGY

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The focus of this program is the development of the chemistry of glucuronides. Objectives include the development of methods to synthesize glucuronides of all types, evaluation and development of new analytical techniques for various kinds of glucuronides, and assessment of the chemical reactivities of these drug metabolites which have potential physiologic or analytical significance. We propose to expand our studies of the electrophillic reactivity of acyl-linked glucuronides, and to evaluate the apparent reactivity of carbinolaminelinked glucuronides. We will develop techniques to distinguish positional ester isomers formed spontaneously by rearrangement of the acyl glycosidic linkage. We will confirm and extend the hypothesis that acyl-linked glucuronides react in vivo with glutathione and with sulfhydryl groups in protein. We will continue to explore and correlate the mass spectral behavior and characteristic fragmentation of different kinds of glucuronides, relying most heavily on electron impact and secondarily on fast atom bombardment and thermospray ionization. We propose to scale up our versatile enzyme-mediated synthetic method by a factor of ten. We will evaluate the utility of glucuronyl transferase immobilized from human liver for synthesis of drug metabolites. We propose to synthesize diglucuronides, quaternary ammonium-linked, carbon-linked, sulfur-linked and amine-linked glucuronides in order to study their chromatographic and mass spectral characteristics and for use as reference compounds for identification of metabolites formed in vivo. Acyl-linked and carbinolamine-linked glucuronides will be synthesized for alkylation studies.