Novel risk assessment of reactive metabolites from discovery to clinical stage

This study was aimed to predict drug-induced liver injury caused by reactive metabolites. Reactive metabolites covalently bind to proteins and could result in severe outcomes in patients. However, the relation between the extent of covalent binding and clinical hepatotoxicity is still unclear. From...

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Bibliographic Details
Published in:Journal of toxicological sciences 2019, Vol.44(3), pp.201-211
Main Authors: Kakutani, Nobuyuki, Nanayama, Toyomichi, Nomura, Yukihiro
Format: Article
Language:English
Subjects:
Assaying
Binding
Body Burden
Chemical and Drug Induced Liver Injury
Covalence
Cyanide
Cysteine
Cysteine - metabolism
Drug Discovery
Exposure
Hepatotoxicity
Humans
In vivo methods and tests
Mathematical analysis
Metabolites
Microsomes, Liver - metabolism
Pharmaceutical Preparations - metabolism
Potassium Cyanide - metabolism
Reactive metabolites
Risk assessment
Risk Assessment - methods
Sensitivity analysis
Trapping
Trapping assay
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Summary:This study was aimed to predict drug-induced liver injury caused by reactive metabolites. Reactive metabolites covalently bind to proteins and could result in severe outcomes in patients. However, the relation between the extent of covalent binding and clinical hepatotoxicity is still unclear. From a perspective of body burden (human in vivo exposure to reactive metabolites), we developed a risk assessment method in which reactive metabolite burden (RM burden), an index that could reflect the body burden associated with reactive metabolite exposure, is calculated using the extent of covalent binding, clinical dose, and human in vivo clearance. The relationship between RM burden and hepatotoxicity in humans was then investigated. The results indicated that this RM burden assessment exhibited good predictability for sensitivity and specificity, and drugs with over 10 mg/day RM burden have high-risk for hepatotoxicity. Furthermore, a quantitative trapping assay using radiolabeled trapping agents ([35S]cysteine and [14C]KCN) was also developed, to detect reactive metabolite formation in the early drug discovery stage. RM burden calculated using this assay showed as good predictability as RM burden calculated using conventional time- and cost-consuming covalent binding assays. These results indicated that the combination of RM burden and our trapping assay would be a good risk assessment method for reactive metabolites from the drug discovery stage.
ISSN:0388-1350
1880-3989
DOI:10.2131/jts.44.201