Cyanide metabolism and physiological disposition

Isom, Gary E.; Borowitz, Joseph L.; Hall, Alan H.

doi:10.1002/9781118628966.ch4

Cited by 6 publications

(6 citation statements)

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“…However, a small metabolite invisible in LC-MS can sometimes be under scrutiny. For example, the toxic cyanide metabolite can be released from alkyl nitriles and sometimes even imidazoisoindoles. , It was also once thought in medicinal chemistry drug design that decyanation metabolism might not occur with aromatic–nitrile groups; however, instances of decyanation from heteroaromatic moieties have been reported (Figure A). , In humans, cyanide can be efficiently detoxified via the enzyme Rhodanese to form thiocyanate but is indistinguishable from endogenous thiocyanate . Radiolabeling nitrile groups with 14 C can be the most direct method of revealing drug-related cyanide release and subsequent formation of the detoxified thiocyanate metabolite.…”

Section: Metabolites Gone “Dark”mentioning

confidence: 99%

“…10,11 In humans, cyanide can be efficiently detoxified via the enzyme Rhodanese to form thiocyanate but is indistinguishable from endogenous thiocyanate. 12 Radiolabeling nitrile groups with 14 C can be the most direct method of revealing drug-related cyanide release and subsequent formation of the detoxified thiocyanate metabolite.…”

Section: Metabolites Gone "Dark"mentioning

confidence: 99%

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The Importance of Tracking “Missing” Metabolites: How and Why?

Wang,

Ballard,

Christopher

et al. 2023

J. Med. Chem.

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Technologies currently employed to find and identify drug metabolites in complex biological matrices generally yield results that offer a comprehensive picture of the drug metabolite profile. However, drug metabolites can be missed or are captured only late in the drug development process. This could be due to a variety of factors, such as metabolism that results in partial loss of the molecule, covalent bonding to macromolecules, the drug being metabolized in specific human tissues, or poor ionization in a mass spectrometer. These scenarios often draw a great deal of attention from chemistry, safety assessment, and pharmacology. This review will summarize scenarios of missing metabolites, why they are missing, and associated uncovering strategies from deeper investigations. Uncovering previously missed metabolites can have ramifications in drug development with toxicological and pharmacological consequences, and knowledge of these can help in the design of new drugs. ■ SIGNIFICANCEMetabolism plays an important role in mediating drug exposure and potential toxicity, and ultimate approval. Nevertheless, identifying metabolic pathways and weighing their relevance can be challenging. This Perspective highlights a myriad of real-world situations where a complete accounting of drug metabolites is achieved only after deeper investigations were made. This review should serve as a new valuable resource, not only to drug metabolism and medicinal chemists but also to toxicologists, regulators, and others involved in drug discovery and early development.

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Section: Metabolites Gone “Dark”mentioning

confidence: 99%

Section: Metabolites Gone "Dark"mentioning

confidence: 99%

The Importance of Tracking “Missing” Metabolites: How and Why?

Wang,

Ballard,

Christopher

et al. 2023

J. Med. Chem.

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“…At high concentrations, thiosulfate is absorbed from the GI tract [11,12], and, under certain conditions, thiosulfate can react non-enzymatically with cyanide to generate thiocyanate [13,14]. Thus, oral/enteral thiosulfate could potentially neutralize cyanide in the GI tract, as well as metabolize systemically absorbed cyanide.…”

Section: Introductionmentioning

confidence: 99%

Oral Glycine and Sodium Thiosulfate for Lethal Cyanide Ingestion

Brenner¹,

Azer²,

Oh³

et al. 2017

J Clinic Toxicol

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Objective: Accidental or intentional cyanide ingestion is an-ever present danger. Rapidly acting, safe, inexpensive oral cyanide antidotes are needed that can neutralize large gastrointestinal cyanide reservoirs. Since humans cannot be exposed to cyanide experimentally, we studied oral cyanide poisoning in rabbits, testing oral sodium thiosulfate with and without gastric alkalization. Setting: University research laboratory.Subjects: New Zealand white rabbits.Interventions: Seven animal groups studied; Groups 1-5 received high dose oral NaCN (50 mg, >LD100) and were treated immediately with oral (via nasogastric tube): 1) saline, 2) glycine, 3) sodium thiosulfate or 4) sodium thiosulfate and glycine, or 5) after 2 min with intramuscular injection of sodium nitrite and sodium thiosulfate plus oral sodium thiosulfate and glycine. Groups 6-7 received moderate dose oral NaCN (25 mg, LD70) and delayed intramuscular 6) saline or 7) sodium nitrite-sodium thiosulfate. Measurements and Main Results:All animals in the high dose NaCN group receiving oral saline or glycine died very rapidly, with a trend towards delayed death in glycine-treated animals; saline versus glycine-treated animals died at 10.3+3.9 and 14.6+5.9 min, respectively (p=0.13). In contrast, all sodium thiosulfate-treated high dose cyanide animals survived (p<0.01), with more rapid recovery in animals receiving both thiosulfate and glycine, compared to thiosulfate alone (p<0.03). Delayed intramuscular treatment alone in the moderate cyanide dose animals increased survival over control animals from 30% to 71%. Delayed treatment in high dose cyanide animals was not as effective as immediate treatment, but did increase survival time and rescued 29% of animals (p<0.01 versus cyanide alone). Conclusions:Oral sodium thiosulfate with gastric alkalization rescued animals from lethal doses of ingested cyanide. The combination of oral glycine and sodium thiosulfate may have potential for treating high dose acute cyanide ingestion and merits further investigation. The combination of systemic and oral therapy may provide further options.

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“…Sodium thiosulfate acts as a sulfur donor for the enzyme rhodanese, which transfers the sulfur to cyanide generating thiocyanate, a relatively non-toxic product [ 5 , 8 – 10 ]. At high concentrations, thiosulfate is absorbed from the GI tract [ 11 , 12 ], and, under certain conditions, thiosulfate can react non-enzymatically with cyanide to generate thiocyanate [ 13 , 14 ]. Thus, oral/enteral thiosulfate could potentially neutralize cyanide in the GI tract, as well as metabolize systemically absorbed cyanide.…”

Section: Introductionmentioning

confidence: 99%

Oral Glycine and Sodium Thiosulfate for Lethal Cyanide Ingestion

Brenner¹,

Azer²,

Oh³

et al. 2017

J Clinic Toxicol

View full text Add to dashboard Cite

Objective Accidental or intentional cyanide ingestion is an-ever present danger. Rapidly acting, safe, inexpensive oral cyanide antidotes are needed that can neutralize large gastrointestinal cyanide reservoirs. Since humans cannot be exposed to cyanide experimentally, we studied oral cyanide poisoning in rabbits, testing oral sodium thiosulfate with and without gastric alkalization. Setting University research laboratory. Subjects New Zealand white rabbits. Interventions Seven animal groups studied; Groups 1–5 received high dose oral NaCN (50 mg, >LD100) and were treated immediately with oral (via nasogastric tube): 1) saline, 2) glycine, 3) sodium thiosulfate or 4) sodium thiosulfate and glycine, or 5) after 2 min with intramuscular injection of sodium nitrite and sodium thiosulfate plus oral sodium thiosulfate and glycine. Groups 6–7 received moderate dose oral NaCN (25 mg, LD70) and delayed intramuscular 6) saline or 7) sodium nitrite-sodium thiosulfate. Measurements and Main Results All animals in the high dose NaCN group receiving oral saline or glycine died very rapidly, with a trend towards delayed death in glycine-treated animals; saline versus glycine-treated animals died at 10.3+3.9 and 14.6+5.9 min, respectively (p=0.13). In contrast, all sodium thiosulfate-treated high dose cyanide animals survived (p<0.01), with more rapid recovery in animals receiving both thiosulfate and glycine, compared to thiosulfate alone (p<0.03). Delayed intramuscular treatment alone in the moderate cyanide dose animals increased survival over control animals from 30% to 71%. Delayed treatment in high dose cyanide animals was not as effective as immediate treatment, but did increase survival time and rescued 29% of animals (p<0.01 versus cyanide alone). Conclusions Oral sodium thiosulfate with gastric alkalization rescued animals from lethal doses of ingested cyanide. The combination of oral glycine and sodium thiosulfate may have potential for treating high dose acute cyanide ingestion and merits further investigation. The combination of systemic and oral therapy may provide further options.

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Cyanide metabolism and physiological disposition

Cited by 6 publications

References 83 publications

The Importance of Tracking “Missing” Metabolites: How and Why?

The Importance of Tracking “Missing” Metabolites: How and Why?

Oral Glycine and Sodium Thiosulfate for Lethal Cyanide Ingestion

Oral Glycine and Sodium Thiosulfate for Lethal Cyanide Ingestion

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