Clinical and experimental studies with sodium aurothiomalate.

Blood and urine gold levels were monitored in patients with rheumatoid arthritis treated with sodium aurothiomalate (Myochrysin). The results failed to demonstrate any association between the measured parameters and patient response. It was concluded that routine determinations of gold concentrations could not be used to predict which patients would fail to respond to treatment or would develop gold toxicity and the concept of therapeutic blood gold concentrations was shown to be invalid. The results were inconsistent with a previously proposed hypothesis that blood gold concentrations are inversely proportional to urinary gold excretion. Concentrations of gold in tissues removed from patients receiving Myochrysin showed that the metal was deposited in synovial tissue during chrysotherapy but that when treatment stopped, this gold was relocated elsewhere. (1,4-[14]C)thiomalic acid and sodium(1,4-[14]C)aurothiomalate were prepared for experimental studies using rats. It was shown that a large proportion of the thiomalic acid remained at the site of intramuscular injection but sodium aurothiomalate was completely absorbed. Excretion and tissue retention of absorbed radioactivity showed that there was similar metabolism of the thiomalate moiety of both compounds suggesting a rapid removal of the gold from aurothiomalate. However, some differences in the urinary radioactive metabolites and tissue distribution pattern indicated that removal of gold was not complete and that some intact aurothiomalate remained. This inference was consistent with the results from in vitro albumin binding experiments which demonstrated the presence of protein bound and non-bound aurothiomalate representing approximately 30% of the initial material. Subcellular distribution and biliary excretion experiments showed that the gold and carbon-14 followed quite separate pathways intracellularly. Gold became concentrated in lysosomes whereas the major organelle which accumulated carbon-14 was the mitochondrion. A wide range of interactions between gold and essential trace metals was demonstrated in a further series of experiments using rats. Accumulation of trace metals in the kidney was accompanied by the induction of a cytosolic gold-binding protein which also contained copper and zinc. Microscopic examination of renal tissue also showed that gold (and possibly copper) was also present within lysosomes of proximal tubular cells. These animals also had evidence of renal tubular dysfunction. The results suggested that interactions between gold and trace metals, particularly copper, could be important in successful chrysotherapy and in gold toxicity. A mechanism for gold toxicity involving copper and metallothionein metabolism is proposed