BIOTRANSFORMATION OF DMSA (SUCCIMER) IN HUMAN

Meso 2,3-dimercaptosuccinic acid (DMSA; Succimer; Chemet) was recently approved by the FDA for the treatment of childhood lead poisoning. As an orphan drug, DMSA was approved despite the fact that relatively little was known about its pharmacokinetics in children. Single-dose studies of DMSA metabolism and pharmacokinetics in children with lead poisoning have revealed that the time course of urinary Pb elimination closely follows the time course of altered DMSA (i.e., mixed disulfide) excretion; it does not follow the time course of elimination of the parent DMSA molecule. In other words, DMSA appears to be a prodrug whose mixed disulfides are the active chelator(s). In addition, we have established that the % of DMSA converted to mixed disulfides varies widely. We propose to test the hypothesis that the efficacy of DMSA, as measured by the decline in blood lead concentration and the rise in urinary Pb excretion, is associated with the extent to which DMSA is converted to its mixed disulfides. We will also determine whether the biotransformation of DMSA varies as a function of ethnicity or age. The proposed study would piggyback onto NIEHS's randomized, placebo controlled trial in children. The Steering Committee of the Randomized Trial has approved this study for subjects enrolled at the Johns Hopkins clinical site and at a second site if needed. We propose to collect a 4-hour urine sample from approximately 200 children for the measurement of Pb, creatinine and unaltered, altered and total DMSA.