PDF(Pubmed)
Abstract：
N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA), group 2A carcinogens, were detected in finished drug products, including metformin, ranitidine, sartans and other drugs which caused multiple recalls in the USA and Europe. Important studies also reported the formation of NDMA when ranitidine and nitrite were added to simulated gastric fluid. Our objective was to screen finished drug products from Europe and USA for nitrosamine impurities and investigate the formation of NDMA in metformin finished drug products when added to simulated gastric fluid. One dosage unit of 30 different commercially available drugs, including metformin, sartans, and ranitidine were tested for NDMA, NDEA, and dimethylformamide (DMF) impurities, using a liquid chromatography-mass spectrometry (LC-MS) method. Then, 6 metformin finished drug products were tested in stomach conditions for 2 h at 37 °C in a 100 mL solution with a pH of 2.5 and different nitrite concentrations (40, 10, 1, 0.1 mM) and tested for NDMA, and DMF using LC-MS. We measured NDMA, NDEA, and DMF in 30 finished drug products. NDMA and DMF were quantified for metformin drug products in simulated gastric fluid with different nitrite concentrations. None of the 30 drugs showed concerning levels of NDMA, NDEA, or DMF when tested as single tablets. However, when metformin tablets are added to simulated gastric fluid solutions with high nitrite concentrations (40 mM and 10 mM), NDMA can reach amounts of thousands of nanograms per tablet. At the closest concentration to physiologic conditions we used, 1 mM, NDMA is still present in the hundreds of nanograms in some metformin products. In this in vitro study, nitrite concentration had a very important effect on NDMA quantification in metformin tablets added to simulated gastric fluid. 1 mM nitrite caused an increase above the acceptable daily intake set by the U.S. Food and Drug Administration (FDA) for some of the metformin drugs. 10 mM, 40 mM nitrite solutions generated NDMA amounts exceeding by more than a hundred times the acceptable daily intake set by the FDA of 96 nanograms. These findings suggest that metformin can react with nitrite in gastric-like conditions and generate NDMA. Thus, patients taking metformin could be exposed to NDMA when high nitrite levels are present in their stomach, and we recommend including a statement within the Patient Package Inserts/Instructions for use.
摘要：
N-亚硝基二甲胺(NDMA)和N-亚硝基二乙胺(NDEA),2A组致癌物，在成品药品中检测到，包括二甲双胍,雷尼替丁,这些药物在美国和欧洲引起了多次召回。重要的研究还报道了当将雷尼替丁和亚硝酸盐添加到模拟胃液中时NDMA的形成。我们的目标是筛选来自欧洲和美国的成品药物中的亚硝胺杂质，并研究添加到模拟胃液中的二甲双胍成品中NDMA的形成。30种不同的市售药物的一个剂量单位，包括二甲双胍,Sartans,和雷尼替丁进行了NDMA测试，NDEA,和二甲基甲酰胺（DMF）杂质，使用液相色谱-质谱（LC-MS）方法。然后，6二甲双胍成品在胃条件下在37°C下在pH为2.5和不同亚硝酸盐浓度（40、10、1、0.1mM）的100mL溶液中测试2小时，并测试NDMA，和DMF使用LC-MS。我们测量了NDMA，NDEA,和30种成品药品中的DMF。在具有不同亚硝酸盐浓度的模拟胃液中对二甲双胍药物产品的NDMA和DMF进行定量。30种药物均未显示有关NDMA水平，NDEA,或DMF，当测试为单一片剂。然而,当将二甲双胍片剂添加到具有高亚硝酸盐浓度（40mM和10mM）的模拟胃液溶液中时，NDMA可以达到每片数千纳克的量。在我们使用的最接近生理条件的浓度下，1mM,NDMA在一些二甲双胍产品中仍然存在数百纳克。在这项体外研究中，亚硝酸盐浓度对二甲双胍片添加到模拟胃液中的NDMA定量具有非常重要的影响。1mM亚硝酸盐引起超过由美国食品和药物管理局(FDA)对一些二甲双胍药物设定的可接受的每日摄入量的增加。10mM,40mM亚硝酸盐溶液产生的NDMA量超过FDA设定的可接受的每日摄入量96纳克的一百倍以上。这些发现表明二甲双胍可以在胃样条件下与亚硝酸盐反应并产生NDMA。因此，服用二甲双胍的患者在胃中存在高亚硝酸盐水平时可能会暴露于NDMA，我们建议在患者包说明书/使用说明书中包括一份声明。
