A quantitative high-throughput trapping assay as a measurement of potential for bioactivation

Meneses-Lorente, Georgina; Sakatis, Melanie Zea; Schulz-Utermoehl, Timothy; Nardi, Claudio De; Watt, Alan P.

doi:10.1016/j.ab.2006.01.016

Cited by 48 publications

(44 citation statements)

References 15 publications

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“…For menthofuran, no cyanide-trapped products have been described previously, the result showing the cyanide being able to trap not only hard iminium ions, but also other types of reactive metabolites. The same was described earlier also by Menenses-Lorente et al 29 who…”

Section: Menthofuran Nicotine and Ethinyl Estradiolsupporting

confidence: 71%

“…Also, a commonly known problem with GSH trapping is that it works well with 'soft' electrophiles, but does not trap effectively some 'hard' electrophiles, such as aldehydes. Therefore, other trapping agents, such as semicarbazide or methoxylamine 27,28 or potassium cyanide, 29,30 that are able to trap hard electrophiles, should also be introduced into the comprehensive screening protocols for reactive metabolites. Recently, other trapping agents such as g-glutamylcysteinyllysine 31 and another peptide consisting of eleven amino acids and containing glutathione with additional nucleophilic residues 32 have also been suggested for trapping simultaneously both soft and hard electrophiles.…”

mentioning

confidence: 99%

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Rapid detection and characterization of reactive drug metabolites in vitro using several isotope‐labeled trapping agents and ultra‐performance liquid chromatography/time‐of‐flight mass spectrometry

Rousu

Pelkonen

Tolonen³

2009

Rapid Comm Mass Spectrometry

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Reactive metabolites are believed to be one of the main reasons for unexpected drug-induced toxicity issues, by forming covalent adducts with cell proteins or DNA. Due to their high reactivity and short lifespan they are not directly detected by traditional analytical methods, but are most traditionally analyzed by liquid chromatography/tandem mass spectrometry (LC/MS/MS) after chemical trapping with nucleophilic agents such as glutathione. Here, a simple but very efficient assay was built up for screening reactive drug metabolites, utilizing stable isotope labeled glutathione, potassium cyanide and semicarbazide as trapping agents and highly sensitive ultra-performance liquid chromatography/time-of-flight mass spectrometry (UPLC/TOFMS) as an analytical tool. A group of twelve structurally different compounds was used as a test set, and a large number of trapped metabolites were detected for most of them, including many conjugates not reported previously. Glutathione-trapped metabolites were detected for nine of the twelve test compounds, whereas cyanide-trapped metabolites were found for eight and semicarbazide-trapped for three test compounds. The high mass accuracy of TOFMS provided unambiguous identification of change in molecular formula by formation of a reactive metabolite. In addition, use of a mass defect filter was found to be a usable tool when mining the trapped conjugates from the acquired data. The approach was shown to provide superior detection sensitivity in comparison to traditional methods based on neutral loss or precursor ion scanning with a triple quadrupole mass spectrometer, and clearly more efficient detection and characterization of reactive drug metabolites with a simpler test setup.

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Section: Menthofuran Nicotine and Ethinyl Estradiolsupporting

confidence: 71%

mentioning

confidence: 99%

Rapid detection and characterization of reactive drug metabolites in vitro using several isotope‐labeled trapping agents and ultra‐performance liquid chromatography/time‐of‐flight mass spectrometry

Rousu

Pelkonen

Tolonen³

2009

Rapid Comm Mass Spectrometry

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“…Meneses-Lorente et al (2006) obtained a similar result for piperidine-containing compounds by using K 14 CN. However, trapping methods alone cannot replace the CB assay, because methods that use nucleophiles can only detect RMs that have the opportunity to diffuse into the incubation medium from the active site of the enzyme.…”

Section: Introductionsupporting

confidence: 64%

Combination of GSH Trapping and Time-Dependent Inhibition Assays as a Predictive Method of Drugs Generating Highly Reactive Metabolites

Nakayama¹,

Takakusa²,

Watanabe³

et al. 2011

Drug Metab Dispos

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“…at ASPET Journals on May 11, 2018 dmd.aspetjournals.org was thereby decreased (Meneses-Lorente et al, 2006). For compounds whose reactive metabolites are not trapped by GSH, like dexamethasone, other trapping assays [such as iminium ion trapping with cyanide (Gorrod et al, 1991) and aldehyde trapping with semicarbazide (Xu et al, 2005), among others] should be conducted to help predict the structure of reactive metabolites.…”

Section: Evaluation Of Drug-induced Liver Injury By Covalent Bindingmentioning

confidence: 99%

Evaluation of the Potential for Drug-Induced Liver Injury Based on in Vitro Covalent Binding to Human Liver Proteins

Usui¹,

Mise²,

Hashizume³

et al. 2009

Drug Metab Dispos

141

123

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ABSTRACT:Prediction of idiosyncratic drug-induced liver injury (DILI) is difficult, and the underlying mechanisms are not fully understood. However, many drugs causing DILI are considered to form reactive metabolites and covalently bind to cellular macromolecules in the liver. The objective of this study was to clarify whether the risk of idiosyncratic DILI can be estimated by comparing in vitro covalent binding (CB) levels among 12 positive compounds (acetaminophen, alpidem, bromfenac, carbamazepine, diclofenac, flutamide, imipramine, nefazodone, tacrine, ticlopidine, tienilic acid, and troglitazone) for DILI and 12 negative compounds (acetylsalicylic acid, caffeine, dexamethasone, losartan, ibuprofen, paroxetine, pioglitazone, rosiglitazone, sertraline, theophylline, venlafaxine, and zolpidem). After incubation with human liver microsomes in the presence of NADPH, there was a large overlap in the distribution of CB amounts between the positive and negative groups. On addition of UDP-glucuronic acid (UDPGA) as a cofactor for glucuronidation, the CB levels of bromfenac and diclofenac were increased. With addition of nucleophilic glutathione (GSH), values for most compounds were decreased. However, separation of the two groups on the basis of CB could not be improved by UDPGA or GSH. Furthermore, CB with human hepatocytes also failed to discriminate positive from negative compounds. Therefore, the CB amount alone is not sufficient for risk assessment of DILI. In contrast, when the CB amount was multiplied by the maximum daily dose, which may reflect maximum hepatic exposure, the two groups did become discriminated. Taken together, our findings suggest that the combination of CB amount and daily dose can estimate the risk of idiosyncratic DILI.

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A quantitative high-throughput trapping assay as a measurement of potential for bioactivation

Cited by 48 publications

References 15 publications

Rapid detection and characterization of reactive drug metabolites in vitro using several isotope‐labeled trapping agents and ultra‐performance liquid chromatography/time‐of‐flight mass spectrometry

Rapid detection and characterization of reactive drug metabolites in vitro using several isotope‐labeled trapping agents and ultra‐performance liquid chromatography/time‐of‐flight mass spectrometry

Combination of GSH Trapping and Time-Dependent Inhibition Assays as a Predictive Method of Drugs Generating Highly Reactive Metabolites

Evaluation of the Potential for Drug-Induced Liver Injury Based on in Vitro Covalent Binding to Human Liver Proteins

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