GOLD-BASED ANTI-ARTHRITIS DRUGS: METABOLISM & TOXICITY

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These drugs have been shown to be effective in induding remission of rheumatoid arthritis (RA). However, very little is known about their metabolism, mode of action or cause of toxicity. In order to better manage the therapy of RA patients and avoid toxic side effects, it is necessary to understand the metabolism and toxicity of these drugs at the molecular level. Metabolism of auranofin, triethylphosphine-S-tetraacetylthioglucosegold(I), an orally administered, experimental drug and myochrisine, sodium gold(I)thiomalate, an injected drug in widespread use will be monitored by the development of new analytical techniques with the necessary sensitivity, generality and rapidity to make drug metabolism studies feasible on groups of patients. The principal technique will utilize an inductively coupled plasma (ICP) emission spectrometer as a detector for high performance liquid chromatography (HPLC). The detector will have sensitivities of 0.01 ppm for gold and 0.05 ppm for sulfur and phosphorus, all of which will be monitored in an element specific mode. Various HPLC column packings will be utilized to separate the drugs and their metabolites from other components of blood, urine and synovial fluids of asthmatic and arthritic patients. The asthmatic cohort will serve as a control group for the arthritic cohort. Comparisons will be made within each group and between groups to determine if there are correlations of qualitative and/or quantitative metabolite distribution in patients with therapeutic efficacy or toxicity. A second analytical technique will use synchrotron radiation X-rays at the Stanford Synchrotron Radiation Laboratory for EXAFS, XANES and DAS studies of metabolites to establish local structure around the gold atoms in metabolites. More classical characterization by NMR and IR spectroscopies and single crystal X-ray diffraction will be used as well. Where necessary for the development of analytical techniques or useful to suggest possible human metabolites, model studies using tissue culture of Chinese hamster ovary cells or animal studies will be undertaken.