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
Absorption is rapid but varies considerably among individuals. Unabsorbed drug is primarily excreted in feces, while absorbed drug is primarily excreted in urine as metabolites. In a study of healthy adult volunteers, absorption was rapid but varied among individuals after a single dose of 16, 32, or 48 mg/kg of (14) Csuccimer, with peak blood radioactivity occurring between 1 and 2 hours. On average, 49% of the radiolabeled dose was excreted: 39% in feces, 9% in urine, and 1% in the lungs as carbon dioxide. Since fecal excretion may represent unabsorbed drug, most of the absorbed drug is excreted by the kidneys. The apparent elimination half-life of the radiolabeled substance in the blood is approximately two days. In other studies of healthy adult volunteers, chemical analysis of dimethyl succinate and its metabolites in urine following a single oral dose of 10 mg/kg showed that dimethyl succinate is rapidly and extensively metabolized. Approximately 25% of the administered dose is excreted in the urine, with peak plasma concentrations and urinary excretion occurring between 2 and 4 hours post-administration. Of the total drug excreted in the urine, approximately 90% is excreted as a mixed metabolite of dimethyl succinate and cysteine disulfide; the remaining 10% is excreted unchanged. Most of the mixed disulfide consists of dimethyl succinate linked to two L-cysteine molecules via disulfide bonds, while the remaining disulfides contain one L-cysteine molecule per dimethyl succinate molecule. This study investigated the urinary excretion of dimethyl succinate following oral administration of 10 mg/kg dimethyl succinate (meta-2,3-dimercaptosuccinic acid) to six healthy men aged 22 to 31 years. Extensive biotransformation occurred in the absorbed dimethyl succinate. Fourteen hours later, only 2.53% of the drug was excreted in the urine as unmodified dimethyl succinate, while 18.1% was excreted in the modified form. Unmodified dimethyl succinate accounted for 12% of the total dimethyl succinate in the urine. Modified dimethyl succinate accounted for 88% of the total dimethyl succinate in the urine. Electrolytic reduction of modified dimethyl succinate converted it to unmodified dimethyl succinate, indicating that the modified dimethyl succinate is a disulfide. Excretion of modified dimethyl succinate peaked 2 to 4 hours after administration. Excretion of zinc, copper, and lead increased slightly but significantly after administration of dimethyl succinate. The chelating agent did not affect the urinary excretion of the other 27 metals and elements.
(14) C DMSA was administered intravenously to mice; mice were frozen by immersion in dry ice/hexane at 6 minutes, 20 minutes, and 1, 3, 9, and 24 hours after injection. Frozen mouse sections were sectioned and subjected to whole-body autoradiography to detect soluble substances. Radioactivity was primarily concentrated in extracellular fluids, such as the subcutaneous tissue, pleural cavity, peritoneal cavity, and periosteal space. Within the first hour after injection, the radioactivity in the periosteal fluid was significantly higher than in other body fluids. Most radioactive substances were excreted via the kidneys and liver. Subcutaneous injection of HgCl₂ one hour before injection of 14C DMSA pretreatment in mice resulted in increased liver radioactivity and decreased lung radioactivity. High concentrations of radioactive substances were observed at the HgCl₂ subcutaneous injection site. The results indicate that most DMSA is present in the extracellular space, but it can also cross cell membranes to some extent. The significant accumulation of DMSA in the periosteal fluid is likely due to the interaction of DMSA with Ca²⁺ in this space. No significant compound retention was found in any tissue, but the retention rate in lung tissue was higher than in most other tissues.

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Metabolism/Metabolites
Chemical analysis of dimethyl succinate and its metabolites (primarily mixed disulfides of L-cysteine) in urine revealed that dimethyl succinate is rapidly and extensively metabolized, but the specific biotransformation sites remain unclear.
Two subjects were orally administered 10 mg/kg DMSA, and urine samples were collected at 1, 2, 4, 6, 9, and 14 hours post-administration. Samples were analyzed using high-performance liquid chromatography (HPLC), ion exchange, and thin-layer chromatography (TLC). Most of the ingested DMSA was present in urine as disulfide bonds with L-cysteine. Electrolytic reduction cleaved these disulfide bonds, resulting in the conversion of the mixed disulfides into DMSA and L-cysteine. Following thiol derivatization, the diamine derivatives were analyzed using HPLC and fluorescence spectroscopy, revealing a high correlation between the excretion of L-cysteine and DMSA in urine. All four metabolites identified in urine contained varying proportions of L-cysteine and DMSA. The results showed that after oral administration of DMSA, it preferentially formed mixed disulfides with L-cysteine rather than DMSA cyclic disulfides. L-cysteine preferentially formed these unique DMSA/mixed disulfides, rather than the usual L-cysteine. The amount of L-cysteine excreted in urine as mixed disulfides was much higher than that excreted as L-cysteine. The increased L-cysteine excretion induced by DMSA exposure suggests that a thiol-disulfide bond exchange occurred between L-cysteine and DMSA, and/or a direct reaction occurred between L-cysteine and DMSA, forming more soluble mixed disulfide bonds.

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Biological Half-Life
48 hours
The apparent elimination half-life of radiolabeled substances in blood is approximately two days.

Hepatotoxicity
In clinical trials on children with lead poisoning, 7% of subjects in the dimethyl succinate treatment group experienced elevated serum transaminase levels, compared to 4% in the placebo group. However, ALT levels exceeding 5 times the upper limit of normal were rare (probability score: E (unlikely to be the cause of clinically significant liver injury)). Interactions The effects of DMSA on the teratogenicity of sodium arsenate were investigated in mice. Pregnant Swiss mice were intraperitoneally injected with 45 mg/kg sodium arsenate on day 8 of gestation. Repeat intraperitoneal injections of 0, 37.5, 75, or 150 mg/kg sodium arsenate were administered at 0, 24, 48, and 72 hours, respectively. Maternal mice were sacrificed on day 18 of gestation. The number of live fetuses, stillborn fetuses, and resorbed fetuses were recorded. Live fetuses were weighed and examined for malformations. Sodium arsenate significantly increased the number of resorbed fetuses and decreased the number of live fetuses and fetal weight. The number of live, stillborn, and resorbed fetuses in mothers treated with 75 or 150 mg/kg DMSA in combination with sodium arsenate was similar to that in the untreated control group, with both fetal weight and number of live fetuses. 37.5 mg/kg DMSA only prevented the sodium arsenate-induced increase in the number of resorbed fetuses. Sodium arsenate significantly increased the incidence of fetal exophthalmos, encephalocele, and rib fusion, and resulted in decreased ossification of the supraoccipital, tarsal, and carpal bones. All doses of DMSA significantly reduced the number of these malformations. The authors concluded that DMSA is effective in preventing embryolethality and teratogenicity of sodium arsenate. The mechanism of action of DMSA may be through increasing arsenic excretion, reducing the amount of arsenic exposed to the embryo to a level insufficient to cause embryotoxicity. Oral DMSA is an effective antagonist of acute oral cadmium chloride. Administration of N-benzyl-N-dithiocarboxy-D-glucosamine sodium (1 mmol/kg) within 8 hours of cadmium ingestion in mice induced cadmium poisoning. Intraperitoneal injection of N-benzyl-N-dithiocarboxy-D-glucosamine sodium combined with oral DMSA resulted in cadmium levels in the kidneys and liver only slightly lower than those achieved with DMSA alone. Both chelation therapy regimens resulted in 80% or more animal survival rates, compared to only 40-50% in untreated animals. Intraperitoneal injection of N-benzyl-N-dithiocarboxy-D-glucosamine is itself a highly effective antagonist against acute or chronic cadmium poisoning induced by intraperitoneal injection of cadmium chloride. Dose-response studies of cadmium mobilization in the liver and kidneys of cadmium-loaded mice demonstrated that N-benzyl-N-dithiocarboxy-D-glucosamine is an effective chelating agent. It is one of the most effective cadmium mobilizing agents developed to date. Results showed that N-benzyl-N-dithiocarboxy-D-glucosamine can remove cadmium from animals that have received long-term cadmium treatment (as described in previous studies). Benzyl-N-dithiocarboxy-D-glucosamine significantly increases cadmium excretion in bile. Nuclear magnetic resonance (NMR) analysis of 113Cd in bile from treated animals and model solutions indicated that this cadmium was undergoing rapid ligand exchange. The effects of DMSA and other chelating agents on gastrointestinal 203Pb absorption and systemic 203Pb retention were investigated. Sprague-Dawley rats (230–260 g) were divided into groups and administered by gavage a solution containing approximately 25 mg/kg Pb, in the form of Pb(NO3)2 plus 15 uCi(203)Pb. Some groups were immediately administered 0.11 mmol/kg of DMSA, calcium edetate, D-penicillamine, or dimercaprol by gavage, while others received the same drugs via intraperitoneal injection. The control group received the drug carrier solution orally or intraperitoneally. Oral administration of DMSA to rats significantly reduced systemic lead retention and gastrointestinal lead absorption (systemic retention + urinary lead excretion). This finding suggests that outpatient treatment of childhood lead poisoning with DMSA is not associated with an increased risk of lead absorption. Rats were intraperitoneally injected with 1 mg/kg cadmium chloride shortly after free access to sodium saccharin solution, under water restriction, with or without subcutaneous DMSA injection. DMSA doses were 25, 50, 100, or 200 mg/kg. DMSA treatment following cadmium injection and saccharin solution ingestion resulted in aversion to both saccharin solution and tap water in mice during the free choice test. A significant negative correlation was found between saccharin intake and DMSA dose, with no effect on total fluid intake during the choice test. Administration of DMSA within 4 hours of cadmium pretreatment attenuated cadmium-induced taste aversion and increased total fluid intake during the choice test. Therefore, it is concluded that taste aversion conditioning is a sensitive behavioral method for detecting cadmium neurotoxicity. For more complete data on interactions of dimethyl succinate (6 types), please visit the HSDB record page.

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Non-human toxicity values
Mouse intraperitoneal injection LD50 > 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.

Dimethyl succinate is a sulfur-containing carboxylic acid compound containing two thiol substituents at the 2 and 3 positions of succinic acid. It is a lead chelating agent and can be used as an antidote for lead poisoning. It has chelating activity. Dimethyl succinate is a dicarboxylic acid, dithiol, and sulfur-containing carboxylic acid. It is a thiol dicarboxylic acid and can be used as an antidote for heavy metal poisoning because it can form strong chelates with heavy metals. Dimethyl succinate is a lead chelating agent. The mechanism of action of dimethyl succinate is the chelation of lead. Dimethyl succinate is an oral heavy metal chelating agent used to treat lead and heavy metal poisoning. Dimethyl succinate is associated with a low incidence of transient elevations in serum transaminases during treatment, but its use is not associated with clinically significant liver damage with jaundice. Dimethyl succinate is an orally effective thiol dicarboxylic acid with heavy metal chelating activity. Dimethyl succinate is a strong chelating agent that binds to heavy metals in the blood, such as lead, forming water-soluble complexes that are then excreted in urine. This helps prevent heavy metal poisoning. Furthermore, dimethyl succinate can chelate alpha particle emitters and the radionuclide polonium-210 (Po-210), thereby increasing their excretion and reducing the toxicity of Po-210. Dimethyl succinate is a mercaptodicarboxylic acid and, due to its ability to form strong chelates with heavy metals, can be used as an antidote for heavy metal poisoning. Indications: For the treatment of lead poisoning in children with blood lead levels above 45 µg/dL. It can also be used to treat mercury or arsenic poisoning. Mechanism of Action: Dimethyl succinate is a heavy metal chelating agent. It binds highly specifically to lead ions in the blood, forming water-soluble complexes that are subsequently excreted by the kidneys. Dimethyl succinate can also chelate mercury, cadmium, and arsenic in this manner. Dimethyl succinate (DMSA) is a lead chelating agent; it forms water-soluble chelates, thereby increasing urinary lead excretion. DMSA forms chelates by coordinating with lead via a sulfur atom and an oxygen atom. The solubility of the lead chelate depends on the degree of ionization of the uncoordinated thiol and carboxylic acid groups. Diamine derivatization, high-performance liquid chromatography (HPLC), fluorescence spectroscopy, and gas chromatography can all be used to analyze DMSA in biological fluids. The acid dissociation constants of meso and racemic DMSA, as well as the formation constants of some DMSA chelates, have been summarized in the literature. DMSA is biotransformed into mixed disulfides in the human body. 14 hours after administration of DMSA (10 mg/kg), only 2.5% of the administered dose is excreted in the urine as unaltered DMSA, while 18.1% is excreted in the urine as altered DMSA. Most of the altered DMSA is present as mixed disulfides in the urine. It consists of DMSA linked to two L-cysteine molecules via disulfide bonds. Each sulfur atom of DMSA is bonded to a cysteine molecule. The remaining 10% of DMSA exists as a cyclic disulfide. Currently, this mixed disulfide has been found in human urine, but not in rabbit, mouse, or rat urine. Clearly, different species exhibit different metabolic pathways for meso-DMSA.

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Therapeutic Use
Antidote; Chelating Agent
No controlled clinical studies have been conducted on dimethyl succinate for the treatment of other heavy metal poisonings. A small number of patients with mercury or arsenic poisoning have received dimethyl succinate treatment. These patients experienced increased urinary excretion of heavy metals and varying degrees of symptom improvement. /This use is not included on the US product label/
Chemet is indicated for the treatment of children with lead poisoning at blood lead levels above 45 μg/dL. Chemet is not indicated for the prevention of lead poisoning in lead-containing environments; when using Chemet, the source of lead exposure should always be identified and eliminated simultaneously. /Uses Included on US Product Label/
Orphan Drug. Drug (Brand Name): Succimer (Chemet). Recommended Use: Prevention of cystine kidney stones in homozygous cystinuria patients prone to stones; mercury poisoning. /Excerpt from Table/
For more complete data on therapeutic uses of Succimer (out of 10), please visit the HSDB record page.

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Drug Warnings
It is unknown whether this drug is excreted into human breast milk. Because many drugs and heavy metals are excreted into human breast milk, breastfeeding women who require Chemet treatment should be advised not to breastfeed.
Upset blood lead levels and related symptoms may rapidly recur after discontinuation of the drug. Blood lead rebound may occur after taking CHEMET as lead redistributes from bone stores to soft tissues and blood. After treatment ends, blood lead levels should be measured at least weekly until blood lead levels stabilize to monitor for rebound. However, more frequent blood lead monitoring should be guided by the severity of lead poisoning (measured by initial blood lead levels and the speed and extent of blood lead rebound). All treated patients should receive adequate fluid replacement. Chemet should be used with caution in patients with impaired renal function. Limited data suggest that Chemet is dialysis-removable, but lead chelates are not. When administering the drug again (and during the initial course of treatment), attention must be paid to potential allergic reactions or other mucocutaneous reactions. Patients requiring repeated use of Chemet should be monitored during each course of treatment. One patient developed recurrent mucocutaneous vesicular rashes during the third course of treatment, with progressively increasing severity, affecting the oral mucosa, urethral meatus, and perianal area. Treatment was initiated for the fourth and fifth courses of treatment. The reactions subsided between courses and after discontinuation. For more complete data on drug warnings for dimethyl succinate (11 in total), please visit the HSDB record page.

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Pharmacodynamics
Dimethyl succinate is an orally effective heavy metal chelator. It forms water-soluble chelates, thereby increasing urinary lead excretion. Dimethyl succinate should not be used for the prevention of lead poisoning in lead-containing environments. Furthermore, when using dimethyl succinate, the source of lead exposure should always be identified and eliminated simultaneously.

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.)