Markedly Elevated Carbamazepine-10,11-epoxide/Carbamazepine Ratio in a Fatal Carbamazepine Ingestion

Russell, Jason L.; Spiller, Henry A.; Baker, Daniel D

doi:10.1155/2015/369707

Cited by 13 publications

(5 citation statements)

References 19 publications

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“…At therapeutic doses, the epoxide concentration is generally about 20 % of CBZ. Over 90 % of the epoxide is further hydrated to trans-10,11-dihydroxy-10,11-dihydro-carbamazepine before excretion in urine ( Russell et al, 2015 ; Bertilsson and Tomson, 1986 ) and this metabolite has been detected at higher concentrations than CBZ in wastewater previously ( Kaiser et al, 2014 ). However, the ratio of CBZ to the epoxide in wastewater was higher than expected at ∼35 (±11) % across all samples.…”

Section: Resultsmentioning

confidence: 99%

High-throughput multi-residue quantification of contaminants of emerging concern in wastewaters enabled using direct injection liquid chromatography-tandem mass spectrometry

Rapp-Wright

Egli

et al. 2020

Journal of Hazardous Materials

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Section: Resultsmentioning

confidence: 99%

High-throughput multi-residue quantification of contaminants of emerging concern in wastewaters enabled using direct injection liquid chromatography-tandem mass spectrometry

Rapp-Wright

Egli

et al. 2020

Journal of Hazardous Materials

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“…Although unlikely, it is possible that a small fraction of patients form a second hapten during CBZ therapy. Russell et al found a plasma CBZE concentration of 54 μg/mL (214 μM) after multiple medication overdose, including 17.8 g of CBZ, which would translate to molar ratios in the range of the in vitro incubations . The relationship between plasma levels of drug/metabolite-protein adduct and susceptibility to hypersensitivity is poorly understood and warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

“…For the first time, [O]CBZ-modified protein was also detected in vivo, in patients prescribed standard CBZ therapy for epilepsy and without any indications of drug toxicity, including any indications of the neurotoxicity that have been associated with unusually high plasma concentrations of CBZE. 70 The His146 [O]CBZ-HSA adduct was identified in plasma samples from all of the 15 patients. There was both inter-and intrapatient variation in relative abundance of the adduct.…”

Section: Chemical Research In Toxicologymentioning

confidence: 99%

Mass Spectrometric Characterization of Circulating Covalent Protein Adducts Derived from Epoxide Metabolites of Carbamazepine in Patients

Yip

Meng

Maggs

et al. 2017

Chem. Res. Toxicol.

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Carbamazepine (CBZ) is an effective antiepileptic drug that has been associated with hypersensitivity reactions. The pathogenesis of those reactions is incompletely understood but is postulated to involve a complex interplay between the drug's metabolism, genetic variation in human leukocyte antigens, and adverse activation of the immune system. Multiple T-cell activation mechanisms have been hypothesized including activation by drug-peptide conjugates derived from proteins haptenated by reactive metabolites. However, definitive evidence of the drug-protein adducts in patients has been lacking. In this study, mass spectrometry was used to characterize protein modifications by microsomally-generated metabolites of CBZ and in patients taking CBZ therapy. CBZ 10,11-epoxide (CBZE), a major electrophilic plasma metabolite of CBZ, formed adducts with glutathione-S-transferase pi (GSTP; Cys47) and human serum albumin (HSA; His146 and His338, but not Cys34) in vitro via notably divergent side-chain selectivity. Both proteins were adducted at the same residues by undefined monoxygenated metabolites ([O]CBZ) when they were incubated with human liver microsomes, NADPH and CBZ. There was also evidence for formation of a CBZ adduct at His146 and His338 of HSA derived via dehydration from an intermediate arene oxide adduct. Glutathione trapping of reactive metabolites confirmed microsomal production of CBZE and indicated simultaneous production of arene oxides. In 15 patients prescribed CBZ therapy, [O]CBZ-modified HSA (His146) was detected in all subjects. The relative amount of adduct was moderately positively correlated with plasma concentrations of CBZ (r = 0.44, p = 0.002) and CBZE (r = 0.35, p = 0.006). Our results have provided the first chemical evidence for microsomal production of [O]CBZ species that are able to escape the microsomal domain to react covalently with soluble proteins. This study has also demonstrated the presence of circulating [O]CBZ-modified HSA in patients without hypersensitivity reactions who were receiving standard CBZ therapy. The implications of those circulating adducts for susceptibility to CBZ hypersensitivity merit further immunological investigation in hypersensitive patients.

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“…Hyperglycemia can accompany CBZ intoxication [7,22,27,28]. Seymour [23] stated that the incidence of hyperglycemia is associated with high drug doses.…”

Section: Discussionmentioning

confidence: 99%

Severe Carbamazepine Intoxication in Children: Analysis of a 40-Case Series

et al. 2016

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BackgroundWe compared the factors that might impact the severity and the prognosis of carbamazepine (CBZ) intoxication in children, as well as the efficacy levels of the treatment options.Material/MethodsDemographic information and clinical and laboratory findings for 40 patients were evaluated retrospectively. Predictive parameters for the development of serious complications were studied.ResultsMedian age of patients was 14 years; 65% of the patients were female. The most common pathological clinical finding and laboratory abnormality were inability to awaken the patient and hyperglycemia (45% and 60%, respectively). The incidences of convulsion, coma, and respiratory failure were 14 (35%), 10 (25%), and 3 (7.5%), respectively. The Glasgow Coma Scale (GCS) scores and pH levels at emergency service admission were significantly lower in the severe intoxication group and the ICU admission group, and body temperature and serum glucose and lactate levels were significantly higher in these groups. A significantly negative correlation was found between the serum CBZ level and the GCS score, but the serum CBZ level was found to be significantly positively correlated with the lactate level.ConclusionsAccording to our study, the GCS score at admission to hospital, the serum CBZ, glucose, pH, and lactate levels, and body temperature might be useful in predicting serious CBZ intoxication and prognosis in pediatric cases. We conclude that invasive treatment methods, such as hemodialysis or albumin-enhanced continuous venovenous hemodialysis, should be used in patients who do not respond to supportive treatment.

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Markedly Elevated Carbamazepine-10,11-epoxide/Carbamazepine Ratio in a Fatal Carbamazepine Ingestion

Cited by 13 publications

References 19 publications

High-throughput multi-residue quantification of contaminants of emerging concern in wastewaters enabled using direct injection liquid chromatography-tandem mass spectrometry

High-throughput multi-residue quantification of contaminants of emerging concern in wastewaters enabled using direct injection liquid chromatography-tandem mass spectrometry

Mass Spectrometric Characterization of Circulating Covalent Protein Adducts Derived from Epoxide Metabolites of Carbamazepine in Patients

Severe Carbamazepine Intoxication in Children: Analysis of a 40-Case Series

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