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.

中文翻译：

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通过结合 HILIC、计算机毒理学和分子对接的综合方法估计尼扎替丁的胃亚硝化能力和产品毒性

首次研究了 H2 受体拮抗剂尼扎替丁 (NZ) 在模拟胃液 (SGJ) 和 WHO 建议条件下对亚硝化的敏感性。为了监测 NZ 的亚硝化能力，根据 FDA 指南优化和验证了亲水相互作用液相色谱 (HILIC) 方法。Cosmosil HILIC® 色谱柱和由乙腈组成的流动相：0.04 M 醋酸盐缓冲液 pH 6.0 (92:8, v/v) 用于在 6 分钟内分离 NZ 及其 N-亚硝基衍生物 (NZ-NO) LOD 分别为 0.02 和 0.1 μg/mL。发现 NZ 在 SGJ 中对亚硝化高度敏感，在 10 分钟内达到 100% 亚硝化，而在 WHO 建议的条件下，160 分钟后仅观察到 18% 的亚硝化。NZ-NO的化学结构通过ESI+/MS澄清。计算机毒理学研究证实了 NZ-NO 的致突变性和毒性。实验证明，抗坏血酸强烈抑制 NZ 的亚硝化作用，表明它们共同给药以防止潜在风险。此外，HILIC 方法对安全、健康和环境的影响得到了三个绿色分析化学指标的良好评价，证明与流行的印象不同，HILIC 方法对环境是绿色的。