Hypoxia-induced modulation of ceramide metabolism: Implications for potential biomarkers and intervention targets

In this paper, the effect of hypoxia on the content of active ceramides in tissues was investigated for the first time, and the pharmacokinetic changes of ceramide C24:1 with hypoxia-protective effects were compared under both normoxic and hypoxic conditions. A UPLC-MS/MS method was developed to determine five ceramides in mouse tissues and plasma. The performance criteria for sensitivity, linearity, matrix effect, recovery, stability, precision, and accuracy were evaluated and found to be within the FDA-recommended guidelines. This method was successfully employed to quantify both endogenous and exogenous ceramides in tissues and plasma. The results revealed tissue-specific changes in endogenous ceramide levels under hypoxia and showed that hypoxia increased the systemic exposure and prolonged the retention of exogenous C24:1 while reducing its clearance. These findings support further investigation of ceramides as potential biomarkers or therapeutic targets for hypoxia-related diseases and provide important in vivo pharmacokinetic data for the development of novel neuroprotective drugs.