Chemical formula: O₃S₂-₂ Molecular mass: 114.144 g/mol PubChem compound: 24478
The mechanism of sodium thiosulfate protection against ototoxicity is not fully understood, but may include increasing levels of endogenous antioxidants, inhibition of intracellular oxidative stress, and direct interaction between cisplatin and the thiol group in sodium thiosulfate to produce inactive platinum species.
Concurrent incubation of sodium thiosulfate with cisplatin decreased the in vitro cytotoxicity of cisplatin to tumour cells; delaying the addition of sodium thiosulfate to these cultures prevented the protective effect.
Exposure to a high dose of cyanide can result in death within minutes due to the inhibition of cytochrome oxidase resulting in arrest of cellular respiration.
Specifically, cyanide binds rapidly with cytochrome a3, a component of the cytochrome c oxidase complex in mitochondria. Inhibition of cytochrome a3 prevents the cell from using oxygen and forces anaerobic metabolism, resulting in lactate production, cellular hypoxia and metabolic acidosis. In massive acute cyanide poisoning, the mechanism of toxicity may involve other enzyme systems as well.
The synergy resulting from treatment of cyanide poisoning with the combination of sodium nitrite and sodium thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.
The primary route of endogenous cyanide detoxification is by enzymatic transulfuration to thiocyanate (SCN-), which is relatively nontoxic and readily excreted in the urine. Sodium thiosulfate is thought to serve as a sulfur donor in the reaction catalyzed by the enzyme rhodanese, thus enhancing the endogenous detoxification of cyanide in the following chemical reaction:
Rhodanese
Na2S2O3 + CN- → SCN- + Na2SO3
Sodium thiosulfate is poorly absorbed after oral administration and has to be administered intravenously. At the end of a sodium thiosulfate intravenous infusion, plasma levels of sodium thiosulfate are maximal and decline rapidly thereafter with a terminal elimination half-life of approximately 50 minutes. A return to pre-dose levels occurs within 3 to 6 hours after infusion. More than 95% of sodium thiosulfate excretion in urine occurs within the first 4 hours after administration.
Hence, there is no plasma accumulation when sodium thiosulfate is administered on 2 consecutive days.
In children and adults, the maximum sodium thiosulfate plasma levels after a 15-minute infusion of a dose equivalent to 12.8 g/m² was approximately 13 mM. Thiosulfate plasma levels change in a dose proportional manner. Age did not appear to influence the maximum plasma levels of sodium thiosulfate or the decline afterwards. A population PK model incorporating growth and maturation variables for the paediatric population showed that the predicted sodium thiosulfate plasma levels at the end of infusion were consistent across the recommended dose levels for the indicated age and body weight ranges.
Sodium thiosulfate does not bind to human plasma proteins. Sodium thiosulfate is an inorganic salt and thiosulfate anions do not readily cross membranes. Hence, the volume of distribution appears largely confined to extracellular spaces and estimated at 0.23 L/kg in adults. In animals, sodium thiosulfate has been found to distribute to the cochlea. Distribution across the blood brain barrier or placenta appears absent or limited. Thiosulfate is an endogenous compound ubiquitously present in all cells and organs. Endogenous serum thiosulfate levels were 5.5 ± 1.8 µM in adult volunteers.
Metabolites of sodium thiosulfate have not been determined as part of clinical studies. Thiosulfate is an endogenous intermediate product of sulfur-containing amino acid metabolism. Thiosulfate metabolism does not involve CYP enzymes; it is metabolised through thiosulfate sulfur transferase and thiosulfate reductase activity to sulfite, which is rapidly oxidised to sulfate.
Sodium thiosulfate (thiosulfate) is excreted through glomerular filtration. After administration, thiosulfate levels in urine are high, and approximately half of the sodium thiosulfate dose is retrieved unchanged in urine, nearly all excreted within the first 4 hours after administration. Thiosulfate renal clearance compared well with inulin clearance as a measure for the GFR.
Excretion of endogenously produced thiosulfate in bile was very low and did not increase after sodium thiosulfate administration. No mass balance studies have been performed, but it is expected that non-renal clearance will mainly result in renal excretion of sulfates. A small part of the sulfane sulfur of sodium thiosulfate may become part of endogenous cellular sulfur metabolism.
In haemodialysis patients, total clearance of sodium thiosulfate was 2.04 ± 0.72 mL/min/kg (off dialysis) compared to 4.11 ± 0.77 mL/min/kg in healthy volunteers. This clearance was essentially similar to the non-renal clearance observed in the healthy volunteers (1.86 ± 0.45 mL/min/kg). In the absence of any glomerular filtration in haemodialysis patients, this only resulted in approximately a 25% increase in the maximum thiosulfate plasma levels and nearly a 2-fold increase in total exposure. The plasma concentration of thiosulfate is deemed to be the most important parameter associated with the efficacy of the product. Moreover, the most frequent adverse reactions are considered to be related to the sodium load with sodium thiosulfate administration and concurrent electrolyte imbalances. Non-clinical studies indicated that dose limiting acute effects were related to the sodium intake. Sodium thiosulfate is only intended to be administered in conjunction with cisplatin chemotherapy. Cisplatin is contraindicated in patients with pre-existing renal impairment and, therefore, in the absence of cisplatin administration sodium thiosulfate would not be administered.
No information is available for use of sodium thiosulfate in patients with hepatic impairment. However, thiosulfate sulfur transferase/reductase activity is ubiquitous, including tissue like red blood cells, liver, kidney, intestine, muscle and brain. Therefore, the changes in thiosulfate pharmacokinetics in hepatically impaired patients are likely limited and without clinical significance.
Sodium thiosulfate does not bind to human plasma proteins. The chemical properties of sodium thiosulfate, along with the observations that sodium thiosulfate does not distribute readily across membrane barriers and is excreted through glomerular filtration, make an interaction with membrane drug transporters unlikely.
Cytochrome P450 enzymes: Sodium thiosulfate is an inducer of CYP2B6 but not of CYP1A2 or CYP3A4. Sodium thiosulfate is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 at clinically relevant concentrations.
Sodium thiosulfate taken orally is not systemically absorbed. Intravenous injection of sodium thiosulfate is 100% bioavailability.
Sodium thiosulfate is rapidly distributed throughout extracellular fluid after IV administration. The volume of distribution of sodium thiosulfate is 150 mL/kg.
Most of the thiosulfate is oxidized to sulfate or is incorporated into endogenous sulphur compounds; a small proportion is excreted through the kidneys.
Approximately 20-50% of exogenously administered thiosulfate is eliminated unchanged via the kidneys. After an intravenous injection of 1 g sodium thiosulfate in patients, the reported serum thiosulfate half-life was approximately 20 minutes. However, after an intravenous injection of a substantially higher dose of sodium thiosulfate (150 mg/kg, that is, 9 g for 60 kg body weight) in normal healthy men, the reported elimination half-life was 182 minutes.
Sodium thiosulfate was not genotoxic in an in vitro bacterial reverse mutation assay (Ames test) with or without metabolic activation and was not clastogenic in an in vitro mammalian cell assay (sister chromatid exchange) using human peripheral lymphocytes.
Long-term studies in animals have not been performed to evaluate the potential carcinogenicity of sodium thiosulfate.
There is insufficient information from animal studies to assess the effects of intravenous infusion of sodium thiosulfate on fertility.
There is insufficient information from animal studies to assess developmental risks with intravenous infusion of sodium thiosulfate.
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