Estimation of nizatidine gastric nitrosatability and product toxicity via an integrated approach combining HILIC, in silico toxicology, and molecular docking

• Published in: Yàowu shi͡p︡in fenxi Vol. 27; no. 4; pp. 915 - 925
• Main Authors: El-Shaheny, Rania, Radwan, Mohamed, Yamada, Koji, El-Maghrabey, Mahmoud
• Format: Journal Article
• Language: English
• Published: China (Republic : 1949- ) Elsevier Taiwan LLC 01.10.2019; Food and Drug Administration; Taiwan Food and Drug Administration
• Subjects: Acetic acid; Acetonitrile; Analytical chemistry; Animals; Ascorbic acid; Buffers (chemistry); Chemicals; Chromatography; Chromatography, High Pressure Liquid; Drugs; Gastric juice; Gastroesophageal reflux; Health hazards; HILIC; Humans; In silico toxicity; Integrated approach; Liability; Liquid chromatography; Molecular Conformation; Molecular docking; Molecular Docking Simulation; Mutagenicity; Neoplasms - chemically induced; Nitrosation; Nitroso Compounds - adverse effects; Nitroso Compounds - chemical synthesis; Nitroso Compounds - chemistry; Nizatidine; Nizatidine - adverse effects; Nizatidine - chemical synthesis; Nizatidine - chemistry; Organic chemistry; Original; Simulated gastric juice; Sodium; Software; Spectrometry, Mass, Electrospray Ionization; Standard deviation; Structure-Activity Relationship; Toxicity; Toxicology; Ulcers; United States > US; Japan; In silico toxicity; Simulated gastric juice; Nitrosation; Nizatidine; HILIC
• ISSN: 1021-9498; 2224-6614
• DOI: 10.1016/j.jfda.2019.08.001

The liability of the H2-receptor antagonist nizatidine (NZ) to nitrosation in simulated gastric juice (SGJ) and under WHO-suggested conditions was investigated for the first time. For monitoring the nitrosatability of NZ, a hydrophilic interaction liquid chromatography (HILIC) method was optimized and validated according to FDA guidance. A Cosmosil HILIC® column and a mobile phase composed of acetonitrile: 0.04 M acetate buffer pH 6.0 (92:8, v/v) were used for the separation of NZ and its N-nitroso derivative (NZ-NO) within 6 min with LODs of 0.02 and 0.1 μg/mL, respectively. NZ was found highly susceptible to nitrosation in SGJ reaching 100% nitrosation in 10 min, while only 18% nitrosation was observed after 160 min under the WHO-suggested conditions. The chemical structure of NZ-NO was clarified by ESI+/MS. In silico toxicology study confirmed the mutagenicity and toxicity of NZ-NO. Experiments evidenced that ascorbic acid strongly suppresses the nitrosation of NZ suggesting their co-administration for protection from potential risks. In addition, the impacts of the HILIC method on safety, health, and environment were favorably evaluated by three green analytical chemistry metrics and it was proved that, unlike the popular impression, HILIC methods could be green to the environment. [Display omitted] •Innovative study of nizatidine nitrosatability in simulated gastric juice (SGJ).•First HILIC method for nizatidine with high sensitivity, selectivity, and speed.•100% nitrosation of nizatidine in SGJ within 10 min was confirmed.•In silico toxicology showed toxicity and mutagenicity of N-nitrosonizatidine.•Inhibitory effect of ascorbic acid on the nitrosation of nizatidine was evaluated.