One common chelating agent for lead poisoning treatment is succinic acid. When compared to the lead group, the red blood cells (RBCs) of lead-exposed mice treated with NAC or Succimer exhibited significantly lower levels of malondialdehyde (MDA) and significantly higher levels of glutathione (GSH). In the red blood cells of lead-exposed rats, succinate administration also led to a decrease in glucose-6-phosphate dehydrogenase (G6PD) activity [1]. Under both lead exposure scenarios, succcamer treatment dramatically lowered blood lead levels; at the conclusion of the treatment, blood lead levels in the high-Pb-succ group were 27% lower than those in the high-Pb group. Given that the high Pb-succ group's brain lead level was 37% lower than that of the high Pb group, succinic acid is an effective way to considerably reduce brain lead [2].

Absorption, Distribution and Excretion
Rapid but variable.
Unabsorbed drug is excreted primarily in feces and absorbed drug is excreted primarily in the urine as metabolites.
In a study performed in healthy adult volunteers, after a single dose of (14)Csuccimer at 16, 32, or 48 mg/kg, absorption was rapid but variable with peak blood radioactivity levels between one and two hours. On average, 49% of the radiolabeled dose was excreted: 39% in the feces, 9% in the urine and 1% as carbon dioxide from the lungs. Since fecal excretion probably represented nonabsorbed drug, most of the absorbed drug was excreted by the kidneys. The apparent elimination half-life of the radiolabeled material in the blood was about two days.
In other studies of healthy adult volunteers receiving a single oral dose of 10 mg/kg, the chemical analysis of succimer and its metabolites in the urine showed that succimer was rapidly and extensively metabolized. Approximately 25% of the administered dose was excreted in the urine with the peak blood level and urinary excretion occurring between two and four hours. Of the total amount of drug eliminated in the urine, approximately 90% was eliminated in altered form as mixed succimer-cysteine disulfides; the remaining 10% was eliminated unchanged. The majority of mixed disulfides consisted of succimer in disulfide linkages with two molecules of L-cysteine, the remaining disulfides contained one L-cysteine per succimer molecule.
The urinary excretion of succimer (meso-2,3-dimercaptosuccinic acid) was studied following oral administration of 10 mg succimer/kg to 6 normal men, aged 22-31 yr. The succimer that was absorbed was extensively biotransformed. After 14 hr only 2.53% of the drug was excreted in the urine as unaltered succimer and 18.1% as altered forms. The unaltered succimer was 12% of the total succimer found in the urine. The altered form(s) of succimer was 88% of the total urinary succimer. The altered succimer can be converted to unaltered succimer by electrolytic reduction, which indicates that the altered forms of succimer are disulfides. The excretion of altered succimer reached a peak between 2 and 4 hr after administration. There were small but significant increases in the excretion of zinc, copper, and lead after succimer. The chelating agent did not influence the urinary excretion of 27 other metals and elements.
(14)C DMSA was administered to mice iv; the mice were frozen by immersion in dry ice/hexane at 6 and 20 min and 1, 3, 9, and 24 hr after injection. The frozen mice were sectioned and processed for whole-body autoradiography for soluble substances. The radioactivity was highly localized in extracellular fluids such as the sc, intrapleural, ip, and periosteal spaces. There was a pronounced accumulation in the periosteal fluid above that in other fluids during the first hour after injection. Most of the radioactivity was eliminated by the kidney and liver. Pretreatment of a mouse with HgCl2 subcutaneously 1 hr before (14)C DMSA produced an increase in radioactivity in the liver and decrease in lung. A high concentration of radioactivity was seen at the sc site of injection of the HgCl2. The results are interpreted to indicate that most of the DMSA is in the extracellular space but that it can cross cellular membranes to some extent. The pronounced accumulation in periosteal fluid may be an interaction of DMSA with Ca2+ in this space. No tissue had a pronounced retention of the compound, but lung retained more than most other tissues.

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Metabolism / Metabolites
Chemical analysis of succimer and its metabolites (primarily mixed disulfides of L-cysteine) in the urine showed that succimer was rapidly and extensively metabolized however the specific site of biotransformation is not known.
/Two/ subjects were given DMSA at 10 mg/kg orally, and urine samples were collected at 1, 2, 4, 6, 9 and 14 hr after administration. Samples were analyzed by HPLC, ion exchange, and TLC techniques. Most of the ingested DMSA was found in the urine in disulfide linkage with L-cysteine. Electrolytic reductive treatment, which breaks disulfide bonds, resulted in the conversion of the mixed disulfides to DMSA and L-cysteine. After the sulfhydryl group was derivatized and the bimane derivatives analyzed by HPLC and fluorescence, a high correlation between the excretion of L-cysteine and DMSA in the urine was evident. Four of the metabolites found in the urine contained L-cysteine and DMSA in different ratios. Results indicated that when DMSA is given orally to humans, it forms mixed disulfides with L-cysteine in preference to the formation of cyclic disulfides of DMSA. L-Cysteine preferentially forms these unique DMSA/mixed disulfides instead of the usual L-cystine. The amount of L-cysteine excreted in the urine as the mixed disulfides far exceeded the amount excreted as L-cystine. This increased excretion of L-cysteine caused by the DMSA exposure implied that a thiol-disulfide exchange between L-cystine and DMSA occurred and/or a direct reaction between L-cysteine and DMSA occurred to form more soluble mixed disulfides.

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Biological Half-Life
48 hours
The apparent elimination half-life of the radiolabeled material in the blood was about two days.

Hepatotoxicity
In clinical trials conducted in children with lead poisoning, serum aminotransferase levels elevations occurred in 7% of succimer- vs 4% of placebo-treated subjects. However, ALT levels above 5 times the upper limit of normal were rare (
Likelihood score: E (unlikely cause of clinically apparent liver injury).

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Interactions
The effect of DMSA on sodium arsenate teratogenicity was studied in mice. Pregnant Swiss mice were injected ip with 45 mg/kg sodium arsenate on day eight of gestation. They were injected ip with 0, 37.5, 75, or 150 mg/kg sodium arsenate 0, 24, 48, and 72 hr later. The dams were killed on gestational day 18. The number of live,dead, and resorbed fetuses was recorded. The live fetuses were weighed and examined for malformations. Sodium arsenate significantly increased the number of resorptions and decreased the number of live fetuses and fetal body weight. The numbers of live, dead, and resorbed fetuses and fetal body weights in dams given 75 or 150 mg/kg DMSA plus sodium arsenate were similar to those of the untreated controls. DMSA at 37.5 mg/kg protected against the sodium arsenate induced increase in number of fetal resorptions only. Sodium arsenate caused a significant increase in the frequency of fetal exophthalmos, exencephaly, rib fusion, and decreases in ossification of the supraoccipital bone, tarsus, and carpus. All DMSA doses significantly reduced the number of these malformations. The authors conclude that DMSA can effectively protect against the embryolethality and teratogenicity of sodium arsenate. DMSA may act by increasing the rate of arsenic excretion to the extent that embryonic exposures to arsenic are too low to cause embryotoxicity.
Orally administered of DMSA is an effective antagonist for acute oral cadmium chloride (1 mmol/kg) intoxication in mice when administered up to 8 hr after cadmium ingestion. Administration of sodium N-benzyl-N-dithiocarboxy-D-glucamine ip along with DMSA orally resulted in kidney and liver cadmium levels only marginally smaller than those obtained with DMSA alone. Both chelation treatment regimens permitted survival of 80% or more of the animals, in comparison to a survival rate of 40-50% in untreated animals. Ip administered N-benzyl-N-dithiocarboxy-D-glucamine by itself is a very effective antagonist for cadmium chloride administered ip in either acute or chronic cadmium intoxication. A dose-response study was made of the mobilization of cadmium from the liver and kidney of cadmium-loaded mice by N-benzyl-N-dithiocarboxy-D-glucamine; this showed that N-benzyl-N-dithiocarboxy-D-glucamine is one of the most effective cadmium mobilizing agents developed to date. /Results indicate/ the ability of N-benzyl-N-dithiocarboxy-D-glucamine to remove cadmium from animals which have been treated with cadmium over an extended period of time /as described in an earlier study/. Benzyl-N-dithiocarboxy-D-glucamine causes a very large increase in the biliary excretion of cadmium. Nuclear magnetic resonance (NMR) spectra of (113)Cd in bile from treated animals and model solutions indicates that such cadmium is undergoing rapid ligand exchange.
The influence of DMSA, as well as other chelating agents, on GI (203)Pb absorption and whole body (203)Pb retention was examined. Groups of Sprague-Dawley rats (230-260 g) were gavaged with a solution containing approximately 25 mg/kg Pb, as Pb(NO3)2 plus 15 uCi (203)Pb. Some groups were then immediately given 0.11 mmol/kg of either DMSA, calcium disodium edetate, D-penicillamine, or dimercaprol by oral gavage, while other groups received the same drugs by ip injection. Control groups received solutions of the drug vehicles orally or ip. Whole body Pb retention and GI Pb absorption (whole body retention + urinary Pb excretion) were significantly decreased in rats that received DMSA orally. This finding implies that the use of DMSA to treat childhood lead intoxication on an outpatient basis is not associated with a risk for increased Pb absorption.
Rats were treated with 1 mg/kg cadmium chloride ip, with or without treatment with DMSA sc shortly after access to a sodium-saccharin solution while on a limited water schedule. Doses were 25, 50, 100, or 200 mg/kg DMSA. Cadmium injection and DMSA treatment after consumption of the saccharin solution each produced an aversion on a free choice trial between the saccharin solution and tap water. Significant inverse relationships between saccharin intake and DMSA dosage were determined without effect on total fluid intake during the choice trial. DMSA produced an attenuation of the cadmium induced flavor aversion and an increase in total fluid intake during the choice trial when administered within 4 hr of cadmium pretreatment. It is concluded that flavor aversion conditioning is a sensitive behavioral test for cadmium neurotoxicity.
For more Interactions (Complete) data for Succimer (6 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Mice ip > 3000 mg/kg

[1]. Antioxidant effects of N-acetylcysteine and succimer in red blood cells from lead-exposed rats. Toxicology. 1998 Jul 17;128(3):181-9.

[2]. Succimer chelation normalizes reactivity to reward omission and errors in lead-exposed rats. Neurotoxicol Teratol. 2007 Mar-Apr;29(2):188-202.

Succimer is a sulfur-containing carboxylic acid that is succinic acid bearing two mercapto substituents at positions 2 and 3. A lead chelator used as an antedote to lead poisoning. It has a role as a chelator. It is a dicarboxylic acid, a dithiol and a sulfur-containing carboxylic acid.
A mercaptodicarboxylic acid used as an antidote to heavy metal poisoning because it forms strong chelates with them.
Succimer is a Lead Chelator. The mechanism of action of succimer is as a Lead Chelating Activity.
Succimer is an oral heavy metal chelating agent used to treat lead and heavy metal poisoning. Succimer has been linked to a low rate of transient serum aminotransferase elevations during therapy, but its use has not been linked to cases of clinically apparent liver injury with jaundice.
Succimer is an orally active mercaptodicarboxylic acid, with heavy metal chelating activity. As a strong chelator, succimer is able to bind to heavy metals, such as lead, in the bloodstream, thereby forming a water-soluble complex that can be eliminated via urinary excretion. This prevents heavy metal poisoning. In addition, succimer is able to chelate the alpha particle emitter and radionuclide polonium Po 210 ((Po-210), thereby increasing its excretion and reducing the toxic effects of Po-210.
A mercaptodicarboxylic acid used as an antidote to heavy metal poisoning because it forms strong chelates with them.

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Drug Indication
For the treatment of lead poisoning in pediatric patients with blood lead levels above 45 µg/dL. May also be used to treat mercury or arsenic poisoning.

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Mechanism of Action
Succimer is a heavy metal chelator. It binds with high specificity to ions of lead in the blood to form a water-soluble complex that is subsequently excreted by the kidneys. Succimer can also chelate mercury, cadmium, and arsenic in this manner.
Succimer is a lead chelator; it forms water soluble chelates and, consequently, increases the urinary excretion of lead.
DMSA chelates by coordination of one sulfur and one oxygen atom with Pb. 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.

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Therapeutic Uses
Antidotes; Chelating Agents
No controlled clinical studies have been conducted with succimer in poisoning with other heavy metals. A limited number of patients have received succimer for mercury or arsenic poisoning. These patients showed increased urinary excretion of the heavy metal and varying degrees of symptomatic improvement. /Use NOT included in US product label/
Chemet is indicated for the treatment of lead poisoning in pediatric patients with blood lead levels above 45 ug/dL. Chemet is not indicated for prophylaxis of lead poisoning in a lead-containing environment; the use of Chemet should always be accompanied by identification and removal of the source of the lead exposure. /Use included in US product label/
Orphan Drug. Drug (Trade Name): Succimer (Chemet). Proposed Use: Prevent cystine kidney stones in patients with homozygous cystinuria who are prone to stone development; mercury intoxication. /From table/
For more Therapeutic Uses (Complete) data for Succimer (10 total), please visit the HSDB record page.

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Drug Warnings
It is not known whether this drug is excreted in human milk. Because many drugs and heavy metals are excreted in human milk, nursing mothers requiring Chemet therapy should be discouraged from nursing their infants.
Elevated blood lead levels and associated symptoms may return rapidly after discontinuation of CHEMET because of redistribution of lead from bone stores to soft tissues and blood. After therapy, patients should be monitored for rebound of blood lead levels, by measuring blood lead levels at least once weekly until stable. However, the severity of lead intoxication (as measured by the initial blood lead level and the rate and degree of rebound of blood lead) should be used as a guide for more frequent blood lead monitoring.
All patients undergoing treatment should be adequately hydrated. Caution should be exercised in using Chemet therapy in patients with compromised renal function. Limited data suggests that Chemet is dialyzable, but that the lead chelates are not.
The possibility of allergic or other mucocutaneous reactions to the drug must be borne in mind on readministration (as well as during initial courses). Patients requiring repeated courses of Chemet should be monitored during each treatment course. One patient experienced recurrent mucocutaneous vesicular eruptions of increasing severity affecting the oral mucosa, the external urethral meatus and the perianal area on the third, fourth and fifth courses of the drug. The reaction resolved between courses and upon discontinuation of therapy.
For more Drug Warnings (Complete) data for Succimer (11 total), please visit the HSDB record page.

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Pharmacodynamics
Succimer is an orally active, heavy metal chelating agent. It forms water soluble chelates and, consequently, increases the urinary excretion of lead. Succimer is not to be used for prophylaxis of lead poisoning in a lead-containing environment. In addition, the use of succimer should always be accompanied by identification and removal of the source of the lead exposure.

C4H6O4S2

182.2

181.97

304-55-2

2418-14-6 (parent cpd)

2724354

White crystals from aqueous methanol
White crystalline powder

1.6±0.1 g/cm3

267.6±40.0 °C at 760 mmHg

196-198ºC (dec.)

115.6±27.3 °C

0.0±1.2 mmHg at 25°C

1.617

1.93

4

6

3

10

139

2

O=C(O)[C@@H](S)[C@@H](S)C(O)=O

ACTRVOBWPAIOHC-XIXRPRMCSA-N

InChI=1S/C4H6O4S2/c5-3(6)1(9)2(10)4(7)8/h1-2,9-10H,(H,5,6)(H,7,8)/t1-,2+

(2S,3R)-2,3-bis(sulfanyl)butanedioic acid

DMSA; Succimer

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 100 mg/mL (~548.79 mM)
H2O : ~4.55 mg/mL (~24.97 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (13.72 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (13.72 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (13.72 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)