meso-2,3-Dimercaptosuccinic acid: chemical, pharmacological and toxicological properties of an orally effective metal chelating agent
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Annu Rev Pharmacol Toxicol. 1990;30:279-306.
meso-2,3-Dimercaptosuccinic acid: chemical, pharmacological and toxicological properties of an orally effective metal chelating agent.
Aposhian HV1, Aposhian MM.
- 1Department of Molecular and Cellular Biology, University of Arizona, Tucson 85721.
The primary purpose of this article is to summarize the recent investigations dealing with the pharmacology and toxicology of meso-2,3-dimercaptosuccinic acid, an orally effective chelating agent.
The need for a better chelating agent for treating young children and pregnant women with lead intoxication has been apparent for some time. Preclinical and clinical evidence now indicate that meso-2,3-dimercaptosuccinic acid, an Orphan Drug, shows the most promise for being effective in this regard. It has an extracellular distribution that may be responsible for its low toxicity compared to other dithiols.
No attempt has been made to compare it in a rigorous and thorough manner with other chelating agents. That has not been the purpose of this review. The advantages of meso-DMSA, however, compared to CaNa2EDTA for the treatment of lead intoxication, have been outlined.
Significant advances have been made recently in elucidating the structures of the metal chelates of DMSA. There is a striking difference between the structures of the lead chelate of meso-DMSA and those of racemic-DMSA.
The former chelates by coordination of one sulfur and one oxygen atom with Pb. The latter can form chelates via the two sulfur atoms or via one oxygen and one sulfur atom. Solubility of the lead chelates depends on the ionization of the noncoordinated thiol and carboxylic acid groups. Bimane derivatization, HPLC, and fluorescence, as well as gas chromatography can be used for analysis of DMSA in biological fluids. The acid dissociation constants for meso- and racemic-DMSA have been summarized from the literature as have the formation constants of some of the DMSA chelates.
DMSA is biotransformed to a mixed disulfide in humans. By 14 hr after DMSA administration (10 mg/kg), only 2.5% of the administered DMSA is excreted in the urine as unaltered DMSA and 18.1% of the dose is found in the urine as altered forms of DMSA. Most altered DMSA in the urine is in the form of a mixed disulfide.
It consists of DMSA in disulfide linkages with two molecules of L-cysteine. One molecule of cysteine is attached to each of the sulfur atoms of DMSA. The remaining 10% of the altered DMSA was in the form of cyclic disulfides of DMSA. So far, the mixed disulfide has been found in human but not in rabbit, mouse, or rat urine.
Apparently there are species differences in how organisms metabolize meso-DMSA.