特殊的药物肝毒性：预防措施及可能的机制

Title:Idiosyncratic Drug Hepatotoxicity: Strategy for Prevention and Proposed Mechanism

Volume: 22 Issue: 4

Author(s): Toshihiko Ikeda

Affiliation:

关键词: 自身免疫反应，化学活性代谢物，共价结合蛋白质，细胞毒性T淋巴细胞，生物标记物，行或不行的决策，人体白细胞抗原，特殊毒性，非特异免疫反应，内在毒性，判断标准，风险估计

摘要: Idiosyncratic drug toxicity has led to the market withdrawal of many drugs in the past. Since animal experiments are not predictive of such toxicity, the pharmaceutical industry continues to seek new methodologies for the prevention of such effects. Although the mechanism of idiosyncratic drug toxicity remains unclear, immune reactions are likely involved. Although drugs with low molecular weights are typically not themselves immunogenic, these drugs may become haptens after being converted to chemically reactive metabolites and becoming covalently cross-linked to proteins. Therefore, screening tests to detect chemically reactive metabolites, most typically by trapping with glutathione, are carried out at early stages of drug development. More quantitative methods are used in later stages of drug development; radioassays for covalent binding (using ¹⁴Cor ³H-labeled compounds) are most frequently employed. A zone classification system created by combining previous assessment criteria for the chemically reactive metabolites in vitro (<50 pmole/mg-protein) and for the dose levels in vivo (<10 mg/day) could be used for risk assessment of drug candidates. A mechanism for idiosyncratic, drug-induced hepatotoxicity is proposed 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 of idiosyncratic drug toxicity and specific human leucocyte antigen genotypes. Therefore, screening of patients for gene biomarkers is expected to reduce the clinical risk of idiosyncratic drug toxicity, thereby prolonging the life cycle of otherwise useful drugs.

Cite this article as:

Toshihiko Ikeda , Idiosyncratic Drug Hepatotoxicity: Strategy for Prevention and Proposed Mechanism, Current Medicinal Chemistry 2015; 22 (4) . https://dx.doi.org/10.2174/0929867321666140916122628