Profiling and Identification of Omeprazole Metabolites in Mouse Brain and Plasma by Isotope Ratio-Monitoring Liquid Chromatography-Mass Spectrometric Method

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.