Metabolic activation and drug‐induced liver injury: <i>in vitro</i> approaches for the safety risk assessment of new drugs

DOI Web Site Web Site 被引用文献5件
  • M. José Gómez‐Lechón
    Unidad de Hepatología Experimental Instituto de Investigación Sanitaria La Fe (IIS La Fe) Valencia Spain
  • Laia Tolosa
    Unidad de Hepatología Experimental Instituto de Investigación Sanitaria La Fe (IIS La Fe) Valencia Spain
  • M. Teresa Donato
    Unidad de Hepatología Experimental Instituto de Investigación Sanitaria La Fe (IIS La Fe) Valencia Spain

書誌事項

公開日
2015-12-22
権利情報
  • http://onlinelibrary.wiley.com/termsAndConditions#vor
DOI
  • 10.1002/jat.3277
公開者
Wiley

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説明

<jats:title>Abstract</jats:title><jats:p>Drug‐induced liver injury (DILI) is a significant leading cause of hepatic dysfunction, drug failure during clinical trials and post‐market withdrawal of approved drugs. Many cases of DILI are unexpected reactions of an idiosyncratic nature that occur in a small group of susceptible individuals. Intensive research efforts have been made to understand better the idiosyncratic DILI and to identify potential risk factors. Metabolic bioactivation of drugs to form reactive metabolites is considered an initiation mechanism for idiosyncratic DILI. Reactive species may interact irreversibly with cell macromolecules (covalent binding, oxidative damage), and alter their structure and activity. This review focuses on proposed <jats:italic>in vitro</jats:italic> screening strategies to predict and reduce idiosyncratic hepatotoxicity associated with drug bioactivation. Compound incubation with metabolically competent biological systems (liver‐derived cells, subcellular fractions), in combination with methods to reveal the formation of reactive intermediates (e.g., formation of adducts with liver proteins, metabolite trapping or enzyme inhibition assays), are approaches commonly used to screen the reactivity of new molecules in early drug development. Several cell‐based assays have also been proposed for the safety risk assessment of bioactivable compounds. Copyright © 2015 John Wiley & Sons, Ltd.</jats:p>

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