Novel risk assessment of reactive metabolites from discovery to clinical stage

• Kakutani Nobuyuki

  Drug Metabolism & Pharmacokinetics Research Laboratories, Central Pharmaceutical Research Institute

• Nanayama Toyomichi

  Drug Metabolism & Pharmacokinetics Research Laboratories, Central Pharmaceutical Research Institute

• Nomura Yukihiro

  Drug Metabolism & Pharmacokinetics Research Laboratories, Central Pharmaceutical Research Institute

抄録

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.

収録刊行物

• Ｔｈｅ　Ｊｏｕｒｎａｌ　ｏｆ　Ｔｏｘｉｃｏｌｏｇｉｃａｌ　Ｓｃｉｅｎｃｅｓ

  Ｔｈｅ　Ｊｏｕｒｎａｌ　ｏｆ　Ｔｏｘｉｃｏｌｏｇｉｃａｌ　Ｓｃｉｅｎｃｅｓ 44 (3), 201-211, 2019

  一般社団法人　日本毒性学会

キーワード

• Reactive metabolites
• Hepatotoxicity
• Body burden
• Trapping assay
• Cysteine
• Cyanide

詳細情報

• CRID: 1390282763102542208
• NII論文ID: 130007609163
• NII書誌ID: AN00002808
• DOI: 10.2131/jts.44.201
• ISSN: 18803989
• ISSN: 03881350
• NDL書誌ID: 029707517
• PubMed: 30842372
• Web Site: https://ndlsearch.ndl.go.jp/books/R000000004-I029707517
• Web Site: https://www.jstage.jst.go.jp/article/jts/44/3/44_201/_pdf
• Web Site: https://search.jamas.or.jp/link/ui/2020013405
• 本文言語コード: en
• データソース種別:
  • JaLC
  • NDL
  • Crossref
  • PubMed
  • CiNii Articles
• 抄録ライセンスフラグ: 使用不可