There exist two enantiomers: (R)‐ and (S)‐rabeprazole. (R)‐rabeprazole offers specific pharmacokinetic advantages and enhanced therapeutic efficacy, warranting further investigation and development. Here, we developed a simple and rapid chiral liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to simultaneously quantify rabeprazole enantiomers and their metabolites (rabeprazole sulfoxide and desmethyl rabeprazole enantiomers) and a LC-MS to quantify rabeprazole thioether. As for the chiral LC-MS/MS method, Chiral-AGP column (150 × 4 mm, 5 μm) was used and its mobile phase was acetonitrile (mobile phase A) and 10 mmol/L ammonium acetate (mobile phase B) (linear gradient profile: 0 min, 10 % B; 5 min, 15 % B; 9 min, 15 % B; 9.01 min, 10 % B; 13 min, 10 % B). The multiple reactions monitoring transitions of m/z 360.3 → 242.1, 376.2 → 240.1, 346.2 → 228.2 and 368.2 → 190.2 were opted for quantifying rabeprazole enantiomers, rabeprazole sulfoxide, desmethyl rabeprazole enantiomers and internal standard omeprazole. The analyte samples were prepared by a simple liquid–liquid extraction method. As for the LC-MS method, analytes were separated on a Inertsil® ODS-3 column (4.6 × 150 mm, 5 μm). The mobile phase was acetonitrile-5 mmol/L ammonium acetate water solution (65:35, v/v). ESI+ was used and ion peaks with m/z 344.2 (rabeprazole thioether) and 285.1 (internal standard diazepam) were monitored. Both these 2 methods were validated for specificity, linearity, precision, accuracy, matrix effect and extraction recovery, and, particularly, the stability of analytes under various conditions. We successfully applied these methods to a 13-week toxicokinetic study of rabeprazole in rats after intravenous administration of (R)- (80, 20, 5 mg/kg/d) and racemic (80 mg/kg/d) rabeprazole sodium. The results showed that rabeprazole and its metabolites did not accumulate in rats. However, desmethyl rabeprazole and rabeprazole thioether showed higher exposure and lower clearance rate in the last administration than in the first one. (R)-rabeprazole showed a higher exposure and a slower elimination rate than (S)-rabeprazole in rats. These findings offer experimental evidence and a theoretical foundation for further preclinical investigations and clinical applications of (R)-rabeprazole.

中文翻译：

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LC-MS/MS 改进大鼠血浆中 (R)-和 (S)-雷贝拉唑钠及其代谢物的定量测定及其在毒代动力学研究中的应用

存在两种对映体：(R)-和(S)-雷贝拉唑。(R)-雷贝拉唑具有特定的药代动力学优势和增强的治疗效果，值得进一步研究和开发。在这里，我们开发了一种简单快速的手性液相色谱-串联质谱（LC-MS/MS）方法来同时定量雷贝拉唑对映体及其代谢物（雷贝拉唑亚砜和去甲基雷贝拉唑对映体）以及LC-MS来定量雷贝拉唑硫醚。手性LC-MS/MS方法采用Chiral-AGP柱（150×4mm，5μm），流动相为乙腈（流动相A）和10mmol/L乙酸铵（流动相B）（线性梯度曲线：0 分钟，10% B；5 分钟，15% B；9 分钟，15% B；9.01 分钟，10% B；13 分钟，10% B）。选择监测 m/z 360.3 → 242.1、376.2 → 240.1、346.2 → 228.2 和 368.2 → 190.2 转变的多反应来定量雷贝拉唑对映体、雷贝拉唑亚砜、去甲基雷贝拉唑对映体和内标奥美拉唑。分析物样品是通过简单的液-液萃取方法制备的。对于 LC-MS 方法，分析物在 Inertsil® ODS-3 色谱柱（4.6 × 150 mm，5 μm）上分离。流动相为乙腈-5 mmol/L 乙酸铵水溶液（65:35，v/v）。使用 ESI+ 并监测 m/z 344.2（雷贝拉唑硫醚）和 285.1（内标地西泮）的离子峰。这两种方法都经过了特异性、线性、精密度、准确度、基质效应和提取回收率的验证，特别是分析物在各种条件下的稳定性。我们成功地将这些方法应用于大鼠静脉注射（R）-（80、20、5 mg/kg/d）和外消旋（80 mg/kg/d）雷贝拉唑钠后为期13周的雷贝拉唑毒代动力学研究。结果表明，雷贝拉唑及其代谢物在大鼠体内没有蓄积。然而，去甲基雷贝拉唑和雷贝拉唑硫醚在最后一次给药中比第一次给药时表现出更高的暴露量和更低的清除率。在大鼠中，(R)-雷贝拉唑比 (S)-雷贝拉唑表现出更高的暴露量和更慢的消除率。这些研究结果为(R)-雷贝拉唑的进一步临床前研究和临床应用提供了实验证据和理论基础。