Spaenig Max, Vogel Matthias, Hansen Tanja, Elenschneider Leroy, Londenberg Anke, Whomsley Rhys, Deppenmeier Uwe, Escher Sylvia E
Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany.
Federal Institute for Drugs and Medical Devices, Bonn, Germany.
ALTEX. 2025 Jun 23. doi: 10.14573/altex.2412061.
N-nitrosamines (NAs) are potentially carcinogenic organic compounds, and nitrosamine drug substance-related impurities (NDSRIs) are currently regulated with class-specific thresholds in the low nanogram range according to the carcinogenic potency categorization approach (CPCA) classification schema. Beyond direct exposure, NDSRIs can form endogenously in the human organism after ingestion of secondary amines. As recently shown, enalapril, propranolol, and fluoxetine form NDSRIs under conditions mimicking the acidic environment in the stomach. The MUTAMIND project investigated whether such endogenously formed NA levels lead to plasma or liver concentrations which align with or exceed the acceptable intake limits based on the current CPCA. A generic physiologically based kinetic (PBK) model was built using compound-specific in vitro ADME parameters such as intestinal permeability and hepatic clearance. The predictions correlated well with measured in vivo ADME data for the data-rich APIs, so the same PBK approach was applied to the corresponding NDSRIs. While the modelling of propranolol was unremarkable, the highest NA conversion rate observed for N-nitrosoenalapril under gastric conditions resulted in plasma and liver levels exceeding those derived from the CPCA threshold by a factor of about 800 and 400, respectively. The long half-life of fluoxetine suggests a risk of bioaccumulation of its nitrosamine with chronic exposure. These findings indicate that PBK modelling could be a valuable tool as part of a weight of evidence approach in contributing to the risk assessment of nitrosamine impurities in pharmaceuticals.
N-亚硝胺（NAs）是潜在的致癌有机化合物，根据致癌潜能分类方法（CPCA）分类模式，目前对与亚硝胺药物相关杂质（NDSRIs）的监管采用低纳克范围内的类别特定阈值。除了直接接触外，摄入仲胺后，NDSRIs可在人体中内源性形成。最近的研究表明，依那普利、普萘洛尔和氟西汀在模拟胃内酸性环境的条件下会形成NDSRIs。MUTAMIND项目研究了这种内源性形成的NA水平是否会导致血浆或肝脏浓度达到或超过基于当前CPCA的可接受摄入限值。利用化合物特异性的体外吸收、分布、代谢和排泄（ADME）参数（如肠道通透性和肝脏清除率）建立了一个通用的基于生理的动力学（PBK）模型。对于数据丰富的活性药物成分（APIs），预测结果与实测的体内ADME数据相关性良好，因此相同的PBK方法被应用于相应的NDSRIs。虽然普萘洛尔的建模结果并不显著，但在胃部条件下观察到的N-亚硝基依那普利的最高NA转化率导致血浆和肝脏水平分别比CPCA阈值高出约800倍和400倍。氟西汀的长半衰期表明，长期接触其亚硝胺存在生物累积风险。这些发现表明，PBK建模作为证据权重方法的一部分，可能是一种有价值的工具，有助于评估药物中亚硝胺杂质的风险。
