Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China.
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China.
J Pharm Biomed Anal. 2020 May 10;183:113146. doi: 10.1016/j.jpba.2020.113146. Epub 2020 Feb 4.
Anaprazole is a novel proton pump inhibitor under development for the treatment of gastric and duodenal ulcers. In the present study, an ultra-performance liquid chromatography-ultraviolet detector/quadrupole time-of-flight mass spectrometry method was developed for the metabolic profiling of human plasma after an oral administration of 40 mg anaprazole. The principal metabolic pathways were identified as sulfoxide reduction to thioether (M8-1), dehydrogenation (M21-1), sulfoxide oxidation to sulfone (M16-3), and sulfoxide reduction with O-demethylation to form carboxylic acid (M7-1). Anaprazole, M8-1, M16-3, M21-1, and M7-1 were selected and further quantified in human plasma by using a rapid and sensitive liquid chromatography-tandem mass spectrometry method. Anaprazole and its four metabolites were extracted from 50 of μL plasma by acetonitrile protein precipitation. Chromatographic retention and separation were achieved on an Kinetex XB-C column (50 mm × 4.6 mm i.d., 5 μm) under gradient elution using 5 mM ammonium acetate with 0.005 % ammonium hydroxide and methanol with 0.005 % ammonium hydroxide as the mobile phase. Positive electrospray ionization was performed using multiple reaction monitoring with transitions of m/z 402.2→242.2, 386.2→226.2, 400.2→242.2, 418.2→282.2, and 386.2→161.2 for anaprazole, M8-1, M21-1, M16-3, and M7-1, respectively. This method was linear in the range of 5.00-3000 ng/mL for anaprazole and 1.00-600 ng/mL for the four metabolites. The lower limit of quantitation was established at 5.00 ng/mL for anaprazole and 1.00 ng/mL for the metabolites. The quantitative method was used to evaluate the pharmacokinetics of anaprazole in phase I clinical trials.
奥美拉唑是一种新型质子泵抑制剂，用于治疗胃溃疡和十二指肠溃疡。在本研究中，建立了一种超高效液相色谱-紫外检测器/四极杆飞行时间质谱法，用于分析人体口服 40mg 奥美拉唑后的血浆代谢产物。主要代谢途径被鉴定为亚砜还原为硫醚（M8-1）、脱氢（M21-1）、亚砜氧化为砜（M16-3）和亚砜还原并去甲基化形成羧酸（M7-1）。选择奥美拉唑、M8-1、M16-3、M21-1 和 M7-1，并通过快速灵敏的液相色谱-串联质谱法进一步定量分析人血浆中的这些物质。用乙腈沉淀蛋白从 50μL 血浆中提取奥美拉唑及其 4 种代谢产物。色谱保留和分离在 Kinetex XB-C 柱（50mm×4.6mm id，5μm）上实现，采用梯度洗脱，以 5mM 乙酸铵，0.005%氨和甲醇，0.005%氨作为流动相。采用正电喷雾电离，多反应监测模式，母离子到子离子的转换分别为 m/z 402.2→242.2、386.2→226.2、400.2→242.2、418.2→282.2 和 386.2→161.2，用于检测奥美拉唑、M8-1、M21-1、M16-3 和 M7-1。该方法在 5.00-3000ng/mL 范围内对奥美拉唑呈线性，在 1.00-600ng/mL 范围内对 4 种代谢产物呈线性。定量下限设定为 5.00ng/mL 用于检测奥美拉唑，1.00ng/mL 用于检测代谢产物。该定量方法用于评价奥美拉唑在 I 期临床试验中的药代动力学。
