Takakusa Hideo, Masumoto Hiroshi, Yukinaga Hideo, Makino Chie, Nakayama Shintaro, Okazaki Osamu, Sudo Kenichi
R&D Division, Drug Metabolism and Pharmacokinetics Research Laboratories, Shinagawa R&D Center, Daiichi Sankyo Co, Ltd, Tokyo, Japan.
Drug Metab Dispos. 2008 Sep;36(9):1770-9. doi: 10.1124/dmd.108.021725. Epub 2008 May 28.
Bioactivation of a drug to a reactive metabolite and its covalent binding to cellular macromolecules is believed to be involved in clinical adverse events, including idiosyncratic drug toxicities (IDTs). For the interpretation of the covalent binding data in terms of risk assessment, the in vitro and in vivo covalent binding data of a variety of drugs associated with IDTs or not were determined. Most of the "problematic" drugs, including "withdrawn" and "warning" drugs, exhibit higher human liver microsome (HLM) in vitro covalent binding yields than the "safe" drugs. Although some of the problematic drugs that are known to undergo bioactivation other than cytochrome P450-mediated oxidation exhibited only trace levels of HLM covalent binding like safe drugs, a rat in vivo covalent binding study could assess the bioactivation of such drugs. Furthermore, the tissue distribution/retention of the drugs was also examined by rat autoradiography (ARG). The residual radioactivity in the liver observed at 72 or 168 h postdose was found to be well correlated with the rat in vivo covalent binding to liver proteins; thus, the in vivo covalent binding yields of the drugs could be extrapolated from the retention profiles observed by means of ARG. Long-term retention of radioactivity in the bone marrow was observed with some drugs associated with severe agranulocytosis, suggesting a spatial relationship between the toxicity profile and drug distribution/retention. Taken together, the covalent binding and tissue distribution/retention data of the various marketed drugs obtained in the present study should be quite informative for the interpretation of data in terms of risk assessment.
药物生物活化生成反应性代谢物并与细胞大分子共价结合被认为与临床不良事件有关，包括特异质性药物毒性（IDTs）。为了从风险评估角度解读共价结合数据，测定了多种与IDTs有关或无关的药物的体外和体内共价结合数据。大多数“问题”药物，包括“撤市”和“警示”药物，其体外人肝微粒体（HLM）共价结合产率高于“安全”药物。尽管一些已知通过细胞色素P450介导的氧化以外途径进行生物活化的问题药物，其HLM共价结合水平仅为痕量，类似于安全药物，但大鼠体内共价结合研究可以评估此类药物的生物活化情况。此外，还通过大鼠放射自显影（ARG）检查了药物的组织分布/滞留情况。给药后72或168小时在肝脏中观察到的残留放射性与大鼠体内药物与肝脏蛋白的共价结合情况高度相关；因此，可以从ARG观察到的滞留情况推断药物的体内共价结合产率。在一些与严重粒细胞缺乏症相关的药物中观察到骨髓中长期存在放射性，这表明毒性特征与药物分布/滞留之间存在空间关系。综上所述，本研究中获得的各种上市药物的共价结合以及组织分布/滞留数据，对于从风险评估角度解读数据应该具有很大的参考价值。
