DMSA, DMPS AND OTHER ORALLY ACTIVE DITHIOL CHELATORS

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DSMA and DMPS are chelating agents that are effective for treating heavy metal intoxication in humans. DMSA, an orphan drug, was approved by the U.S. FDA in January 1991 for treating childhood lead poisoning and is expected to be the drug of choice for this. DMPS has been approved by the German FDA as a mercury antidote. Highly sensitive and selective analytical assays involving bimane derivatization, HPLC, and fluorescence detection have been developed in this lab and have resulted in the safe analytical determination, in humans, of these chelating agents and their metabolites. The more knowledge available about any drug, the better and safer therapeutic use can be made of it. After oral administration to humans, DMSA appears to be transported to the kidney by plasma albumin where it appears to be biotransformed to DMSA-cysteine mixed disulfides. This brings up the question as to whether chelation only takes place in the kidney - a question that will be investigated. There appears to be a major species difference in the biotransformation of DMSA. Mice, rats, and rabbits do not metabolize DMSA to the DMSA-cysteine mixed disulfide. The biotransformation of DMSA will continue to be elucidated in humans and that for DMPS will begin. The DMPS metal chelates of divalent Pb, Hg, Cd, and Ni will be synthesized and their structures determined. Metal chelates of DMPS and DMSA will be isolated from the urine and their structures determined. The redox potentials of DMSA and DMPS will be determined. Preliminary results indicate a DMPS challenge test to detect "mini-exposure" to mercury is promising. This is an interdisciplinary investigation in which a molecular and cellular biologist/pharmacologist, a chemist, and a physician will interact to gain basic and applied information, very often in humans, about these chelating agents. The long-term goal is to study the toxicological and pharmacological properties of these orally effective therapeutic agents so that safe chelating agents will be available for human therapy.