| Metabolism of Meso-2,3-Dimercaptosuccinic Acid in Lead-Poisoned Children and Normal Adults
Patrick Asiedu,1 Thomas Moulton,2 Conrad B. Blum,3 Erlinda Roldan,4 Nancy J. LoIacono,1 and Joseph H. Graziano1,2 Departments of 1Pharmacology, 2Pediatrics, and 3Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032 USA
4Deparment of Pediatrics, Woodhull Hospital, Brooklyn, NY 11201 USA Abstract
Meso-2,3-dimercaptosuccinic acid (DMSA, or succimer) is an oral chelating agent for heavy-metal poisoning. While studying the urinary elimination of unaltered DMSA, altered DMSA (i.e., its mixed disulfides) , and lead in children with lead poisoning, we observed a pattern of urinary drug elimination after meals suggestive of enterohepatic circulation. The excretion of lead in urine patterned the elimination of altered DMSA rather than the parent molecule. In addition, the half-life of elimination of DMSA via the kidney was positively associated with blood lead concentration. Two additional cross-over studies of DMSA kinetics were conducted in normal adults to confirm the presence of enterohepatic circulation of DMSA after meals. In one, increases in plasma total DMSA concentration were observed after meals in all six subjects ; these increases were prevented by cholestyramine administration 4, 8, and 12 hr after DMSA. In the second, the administration of neomycin also prevented increases in DMSA after meals. These studies indicate that 1) a metabolite(s) of DMSA undergoes enterohepatic circulation and that microflora are required for DMSA reentry ; 2) in children, moderate lead exposure impairs renal tubular drug elimination ; and 3) a metabolite of DMSA appears to be an active chelator. Key words: chelation, enterohepatic circulation, lead, meso-2, 3-dimercaptosuccinic acid, pharmacokinetics, succimer. Environ Health Perspect 103:734-739 (1995) Address correspondence to J. H. Graziano, Department of Pharmacology, Columbia University Medical Center, 630 West 168th Street, New York, NY 10032 USA. P. Asiedu is currently at the Department of Medicine, Mayo Graduate School of Medicine, 200 First Street, SW, Rochester, MN 55905 USA. We gratefully acknowledge H. Vas Aposhian and Rich Maiorino of the University of Arizona for their generous assistance in helping us to establish the DMSA assay and for their analyses of a subset of samples reported here. We also thank Alan Jeffrey for his advice and assistance. Finally, we express our heartfelt thanks to the expert nursing staffs of the Division of Pediatric Hematology and the Pediatric and Adult Clinical Research Centers. This work was supported by grants ES 05025, ES 03460, RR 00645, and the Lucille P. Markey Program in Molecular Toxicology and Nutrition. Received 30 November 1994 ; accepted 30 March 1995.
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