Metabolism of meso-2,3-dimercaptosuccinic acid in lead-poisoned children and normal adults.
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 crossover 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.
Asiedu
P
P
Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Moulton
T
T
Blum
C B
CB
Roldan
E
E
Lolacono
N J
NJ
Graziano
J H
JH
D000328:Adult; D002648:Child; D002675:Child, Preschool; D002792:Cholestyramine Resin / Q000494:pharmacology; D018592:Cross-Over Studies; D004435:Eating; D005260:Female; D006801:Humans; D007223:Infant; D007854:Lead / Q000097:blood / Q000652:urine; D007855:Lead Poisoning / Q000097:blood / Q000378:metabolism* / Q000652:urine; D008102:Liver Circulation; D008297:Male; D009355:Neomycin / Q000494:pharmacology; D010865:Pilot Projects; D004113:Succimer / Q000008:administration & dosage / Q000378:metabolism*
D002792:Cholestyramine Resin; D007854:Lead; D004113:Succimer; D009355:Neomycin