Tsuji Genichiro, Kurohara Takashi, Shoda Takuji, Yokoo Hidetomo, Ito Takahito, Masada Sayaka, Uchiyama Nahoko, Yamamoto Eiichi, Demizu Yosuke
National Institute of Health Sciences.
Chem Pharm Bull (Tokyo). 2024;72(2):166-172. doi: 10.1248/cpb.c23-00550.
The recent discovery of N-nitrosodimethylamine (NDMA), a mutagenic N-nitrosamine, in pharmaceuticals has adversely impacted the global supply of relevant pharmaceutical products. Contamination by N-nitrosamines diverts resources and time from research and development or pharmaceutical production, representing a bottleneck in drug development. Therefore, predicting the risk of N-nitrosamine contamination is an important step in preventing pharmaceutical contamination by DNA-reactive impurities for the production of high-quality pharmaceuticals. In this study, we first predicted the degradation pathways and impurities of model pharmaceuticals, namely gliclazide and indapamide, in silico using an expert-knowledge software. Second, we verified the prediction results with a demonstration test, which confirmed that N-nitrosamines formed from the degradation of gliclazide and indapamide in the presence of hydrogen peroxide, especially under alkaline conditions. Furthermore, the pathways by which degradation products formed were determined using ranitidine, a compound previously demonstrated to generate NDMA. The prediction indicated that a ranitidine-related compound served as a potential source of nitroso groups for NDMA formation. In silico software is expected to be useful for developing methods to assess the risk of N-nitrosamine formation from pharmaceuticals.
近期在药品中发现了具有致突变性的N-亚硝基二甲胺（NDMA），这对相关药品的全球供应产生了不利影响。N-亚硝基胺的污染使研发或药品生产的资源和时间被转移，成为药物开发的一个瓶颈。因此，预测N-亚硝基胺污染风险是防止药品被DNA反应性杂质污染以生产高质量药品的重要一步。在本研究中，我们首先使用专家知识软件在计算机上预测了模型药物（即格列齐特和吲达帕胺）的降解途径和杂质。其次，我们通过一个示范试验验证了预测结果，该试验证实了在过氧化氢存在下，尤其是在碱性条件下，格列齐特和吲达帕胺降解会形成N-亚硝基胺。此外，使用雷尼替丁（一种先前已证明会生成NDMA的化合物）确定了降解产物形成的途径。预测表明，一种与雷尼替丁相关的化合物是NDMA形成过程中潜在的亚硝基来源。计算机软件有望用于开发评估药品中N-亚硝基胺形成风险的方法。
