特異体質性の薬剤性肝障害-仮説の提案と医薬品開発における予防戦略

Drug-induced liver injury (DILI) with idiosyncratic nature has led to the market withdrawal of many drugs in the past. Since animal experiments are not predictive of this type of toxicity, the pharmaceutical industry continues to seek new methodologies for the prevention of such toxicity. Although the mechanism of the idiosyncratic drug toxicity including DILI remains unclear, immune reactions are likely involved. Drugs with low molecular weights, generally thought non-immunogenic, could become haptens after being converted to chemically reactive metabolites and binding covalently to proteins. Therefore, screening tests to detect chemically reactive metabolites, most frequently by trapping with glutathione, are carried out at early stages of drug development. More quantitative methods are needed in later stages of drug development; radioassays for covalent binding (using ¹⁴C- or ³H-labeled compounds) are employed. A zone classification system could assess a risk of drug candidates for idiosyncratic DILI by plotting the clinical dose levels against the amount of the chemically reactive metabolites bound to proteins in vitro. We propose a mechanism for idiosyncratic DILI by analogy to virus-induced hepatitis, where cytotoxic T lymphocytes play an important role. We suggest that idiosyncrasy reflects the involvement of polymorphisms in the human leucocyte antigen-encoding loci. In fact, a strong correlation has been found between idiosyncratic DILI and specific human leucocyte antigen genotypes. Therefore, screening of patients for gene biomarkers is expected to reduce the clinical risk of idiosyncratic DILI, thereby prolonging the life cycle of otherwise useful drugs.