Mobilization and removal of methylmercury in the dog during extracorporeal complexing hemodialysis with 2,3-dimercaptosuccinic acid (DMSA)

Dimercaptosuccinic acid (DMSA), a water soluble dithiol complexing agent exhibiting low systemic toxicity, was found to have a high affinity for methylmercury when compared to a representative monothiol complexing agent in an in vitro whole-blood system. Utilizing ²⁰³Hg-labeled methylmercury, MDSA was over 10 times more effective than D-penicillamine at effecting a redistribution of ²⁰³Hg from protein binding sites into a complexed, soluble form. This prompted studies to evaluate the effectiveness of DMSA in the extracorporeal complexing hemodialysis for the removal of methylmercury in the dog. Extracorporeal complexing hemodialysis incorporates the addition of a complexing agent directly into blood within the extracorporeal circuit before the entry of blood into the hemodialyzer. In comparing the effects of DMSA and cysteine-complexing hemodialysis in dogs dosed previously with ²⁰³Hg-labeled methylmercury, there was a 1.6-fold greater removal of ²⁰³Hg from blood when the dithiol complexing agent was infused; 58% of the ²⁰³Hg was cleared from blood passing through the hemodialyzer using DMSA compared to 38% for cysteine. At the same time, the clearance of free DMSA was not significantly different from that of free cysteine. During DMSA extracorporeal complexing hemodialysis, there was a dramatic shift in systemic methylmercury distribution. Approximately 80% of the ²⁰³Hg in whole blood was associated with the plasma fraction. This was coincident with a similarly dramatic increase in urinary excretion of ²⁰³Hg which in some cases exceeded the removal rate of ²⁰³Hg by the hemodialyzer. Combined urinary and dialyzer output of ²⁰³Hg resulted in significant differences in ²⁰³Hg half-times during treatment of 0.25 days for DMSA-complexing hemodialysis and 1.3 days for cysteine-complexing hemodialysis, compared to 137 days in untreated dogs. No serious adverse effects were observed during treatment. The technique of DMSA-complexing hemodialysis provides a means of rapid removal of methylmercury in the dog model. Excretion data suggest that aggressive systemic treatment with DMSA may be a useful therapeutic alternative when rapid removal of the metal intoxicant is desired and hemodialysis equipment and expertise is unavailable.