The chemical formula of sodium thiosulfate is Na2S2O3. The molecular weight of sodium thiosulfate is 248 Da. It forms a pentahydrate that is highly water soluble.
The sulfur provided by sodium thiosulfate binds to cyanide with the help of rhodanese (cyanide sulfur transferase) and mercaptopyruvate sulfur transferase.8,36,38 Sulfane sulfur (a divalent sulfur bound to one other sulfur) is the only sulfur that reacts with cyanide to produce thiocyanate, which is minimally toxic and renally eliminated. In several animal models, sodium thiosulfate protects against several minimum lethal doses of cyanide.16,20 The addition of rhodanese increases the efficacy of sodium thiosulfate, but the use of rhodanese is impractical in the clinical setting.20,37 The cationic site on rhodanese is crucial to cleaving the sulfur–sulfur bond of thiosulfate and forming a sulfur–rhodanese complex that readily reacts with cyanide.38
Rhodanese is probably not solely responsible for sulfur–sulfur bond cleavage, as rhodanese is largely a mitochondrial enzyme found in the liver and skeletal muscle, and sodium thiosulfate is a divalent ion that poorly crosses membranes.12,20,25,36,38 It is also suggested that both mercaptopyruvate sulfurtransferase and rhodanese are involved in the formation of sulfane sulfur in the liver from sodium thiosulfate, and that serum albumin then carries the sulfane sulfur from the liver to other organs. When cyanide is present, albumin delivers this sulfur to cyanide, forming thiocyanate.17,36,37, and 38
Pharmacokinetics and Pharmacodynamics
Sodium thiosulfate is a large divalent anion. Canine studies suggest that sodium thiosulfate rapidly distributes into the extracellular space and then slowly into the cell, perhaps with a carrier facilitating entry into the mitochondria.15,25 When administered prior to cyanide, thiosulfate converted more than 50% of the cyanide to thiocyanate within 3 minutes and increased the endogenous conversion rate more than 30 times.35 A canine model employing continuous intravenous (IV) infusion of cyanide to induce a respiratory arrest, demonstrated that the IV administration of 500 mg/kg of sodium thiosulfate decreased the serum cyanide concentration and restored respiration within 3 minutes.10 Thiosulfate is filtered and secreted in the kidney. At low serum concentrations, thiosulfate is largely reabsorbed, whereas at high serum concentrations filtration and secretion predominate.14,25
A volunteer study examined the pharmacokinetics of sodium thiosulfate and the fate of thiosulfate.16,25 After injection of 150 mg/kg, the volume of distribution (Vd) was 0.15 L/kg, the distribution half-life was 23 minutes, and the elimination half-life was 3 hours. The peak serum thiosulfate concentration rose 100 fold. Approximately 50% of the drug was eliminated in 18 hours, most of that within the first 3 hours. Baseline thiosulfate concentrations were higher in starved patients and children, presumably because of their higher protein metabolism to thiosulfate.16 Normally, the kidney actively reabsorbs thiosulfate, but this study found that with exogenous administration, thiosulfate clearance equaled creatinine clearance.16
The study of thiosulfate as a cisplatin neutralizer demonstrated a half-life of 80 minutes, and that renal clearance accounted for only 30% of the total clearance.31 Oral sodium thiosulfate is poorly absorbed and acts as a laxative.25
A pharmacokinetic study was conducted in healthy volunteers as well as hemodialysis (HD) patients both on and off of HD.13 Eight grams of sodium thiosulfate was diluted in 50 mL of 0.9% NaCl and infused over 8 minutes. The use of a population pharmacokinetic model revealed a small Vd (0.226 L/kg), a nonrenal clearance similar to the renal clearance accounting for about 50% of the elimination in both healthy volunteers and HD patients. Total body clearance in the HD patients undergoing HD was double that of the same patients not receiving HD. A one compartment distribution model was assumed due to the absence of rebound concentrations after HD ended. Oral bioavailability was only about 8% and was calculated after 5 g of the IV solution was diluted in 100 mL of water and ingested rapidly.