Shin Seok-Ho, Park Yuri, Park Min-Ho, Byeon Jin-Ju, Lee Byeong Ill, Choi Jangmi, Shin Young G
College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, Daejeon 34134, Korea.
Life (Basel). 2020 Jul 19;10(7):115. doi: 10.3390/life10070115.
Neuro-inflammation is known to be one of the pathogenesis for the degenerative central nervous system (CNS) disease. Recently various approaches for the treatment of brain diseases by controlling neuro-inflammation in the brain have been introduced. In this respect, there is a continuous demand for CNS drugs, which could be safer and more effective. Omeprazole, a well-known proton-pump inhibitor (PPI) is generally prescribed for the treatment of peptic ulcer. In addition to the anti-gastric acid secretion mechanism, recent studies showed that omeprazole or PPIs would likely have anti-inflammation effects in vitro and in vivo, but their effects on anti-inflammation in brain are still unknown. In this study, omeprazole and its metabolites in a mouse's brain after various routes of administration have been explored by stable isotope ratio-patterning liquid chromatography-mass spectrometric method. First, a simple liquid chromatography-mass spectrometric (LC-MS) method was established for the quantification of omeprazole in mouse plasma and brain. After that, omeprazole and its stable isotope (D3-omeprazole) were concomitantly administered through various routes to mice in order to identify novel metabolites characteristically observed in the mouse brain and were analyzed using a different LC-MS method with information-dependent analysis (IDA) scan. With this unique approach, several new metabolites of omeprazole were identified by the mass difference between omeprazole and stable isotope in both brain and plasma samples. A total of seventeen metabolites were observed, and the observed metabolites were different from each administration route or each matrix (brain or plasma). The brain pharmacokinetic profiles and brain-to-plasma partition coefficient (Kp) were also evaluated in a satellite study. Overall, these results provide better insights to understand the CNS-related biological effects of omeprazole and its metabolites in vivo.
神经炎症被认为是中枢神经系统（CNS）退行性疾病的发病机制之一。最近，已经引入了各种通过控制脑部神经炎症来治疗脑部疾病的方法。在这方面，对更安全、更有效的中枢神经系统药物的需求持续存在。奥美拉唑是一种著名的质子泵抑制剂（PPI），通常用于治疗消化性溃疡。除了抗胃酸分泌机制外，最近的研究表明，奥美拉唑或质子泵抑制剂在体外和体内可能具有抗炎作用，但其对脑部抗炎作用仍不清楚。在本研究中，采用稳定同位素比模式液相色谱 - 质谱法探索了奥美拉唑及其代谢产物在小鼠经各种给药途径后的脑部情况。首先，建立了一种简单的液相色谱 - 质谱（LC - MS）方法用于定量小鼠血浆和脑中的奥美拉唑。之后，将奥美拉唑及其稳定同位素（D3 - 奥美拉唑）通过各种途径同时给予小鼠，以鉴定在小鼠脑中特有的新型代谢产物，并使用具有信息依赖分析（IDA）扫描的不同LC - MS方法进行分析。通过这种独特的方法，通过脑和血浆样品中奥美拉唑与稳定同位素之间的质量差异鉴定了几种奥美拉唑的新代谢产物。总共观察到17种代谢产物，观察到的代谢产物因给药途径或基质（脑或血浆）而异。在一项卫星研究中还评估了脑药代动力学概况和脑 - 血浆分配系数（Kp）。总体而言，这些结果为理解奥美拉唑及其代谢产物在体内的中枢神经系统相关生物学效应提供了更好的见解。
