Nakayama Shintaro, Atsumi Ryo, Takakusa Hideo, Kobayashi Yoshimasa, Kurihara Atsushi, Nagai Yoko, Nakai Daisuke, Okazaki Osamu
Drug Metabolism and Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan.
Drug Metab Dispos. 2009 Sep;37(9):1970-7. doi: 10.1124/dmd.109.027797. Epub 2009 Jun 1.
The risk of idiosyncratic drug toxicity (IDT) is of great concern to the pharmaceutical industry. Current hypotheses based on retrospective studies suggest that the occurrence of IDT is related to covalent binding and daily dose. We determined the covalent binding of 42 radiolabeled drugs in three test systems (human liver microsomes and hepatocytes in vitro and rat liver in vivo) to assess the risk of IDT. On the basis of safety profiles given in official documentation, tested drugs were classified into the safety categories of safe, warning, black box warning, and withdrawn. The covalent binding in each of the three test systems did not distinguish the safety categories clearly. However, when the log-normalized covalent binding was plotted against the log-normalized daily dose, the distribution of the plot in the safety categories became clear. An ordinal logistic regression analysis indicated that both covalent binding and daily dose were significantly correlated with safety category and that covalent binding in hepatocytes was the best predictor among the three systems. When two separation lines were drawn on the correlation graph between covalent binding in human hepatocytes and daily dose by a regression analysis to create three zones, 30 of 37 tested drugs were located in zones corresponding to their respective classified safety categories. In conclusion, we established a zone classification system using covalent binding in human hepatocytes and daily dose for the risk assessment of IDTs.
特异质性药物毒性（IDT）风险是制药行业极为关注的问题。基于回顾性研究的当前假说表明，IDT的发生与共价结合及每日剂量有关。我们测定了42种放射性标记药物在三种测试系统（体外人肝微粒体和肝细胞以及体内大鼠肝脏）中的共价结合情况，以评估IDT风险。根据官方文件给出的安全性概况，将受试药物分为安全、警告、黑框警告和撤市的安全类别。三种测试系统中每种系统的共价结合情况均未明确区分安全类别。然而，当将对数归一化的共价结合与对数归一化的每日剂量作图时，安全类别中该图的分布变得清晰。有序逻辑回归分析表明，共价结合和每日剂量均与安全类别显著相关，并且肝细胞中的共价结合是三种系统中最佳的预测指标。通过回归分析在人肝细胞中共价结合与每日剂量之间的相关图上绘制两条分隔线以创建三个区域时，37种受试药物中有30种位于与其各自分类安全类别相对应的区域。总之，我们建立了一种使用人肝细胞中共价结合和每日剂量的区域分类系统，用于IDT的风险评估。
