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Fingolimod is a sphingosine 1-phosphate-receptor modulator approved for the oral treatment of relapsing–remitting multiple sclerosis (RRMS), a form of MS characterized by a pattern of exacerbation of neurological symptoms followed by recovery. Here, we validated a simple and rapid liquid chromatography–tandem mass spectrometry method for the measurement of the concentrations of Fingolimod and its active metabolite Fingolimod-Phosphate (Fingolimod-P) in human plasma. The lower limits of quantification were set at 0.3 and 1.5 ng/mL for Fingolimod and Fingolimod-P, respectively, and the linearity was in the range 0.3–150 ng Fingolimod/mL and 1.5–150 ng Fingolimod-P/mL. After protein precipitation, the extraction recoveries of both analytes were always above 60% with minimal matrix effect. The method was accurate and precise, satisfying the criteria set in the European Medicine Agency guidelines for bioanalytical method validation. The method was then applied to measure Fingolimod and Fingolimod-P concentrations in the plasma of 15 RRMS patients under chronic treatment with Fingolimod, administered daily at the dose of 0.5 mg for up to 24 months. No significant differences were observed between samples collected at 6, 12 and 24 months for both analytes, indicating that the drug’s bioavailability was unaffected by multiple daily doses up to 24 months. The levels of Fingolimod-P were about two-fold higher than the levels of the parent compound. The availability of this analytical method can allow the monitoring of the impact of plasma levels of the drug and its metabolite on inter-individual variability in clinical responses.

Imbalance in the oxidative status in neurons, along with mitochondrial damage, are common characteristics in some neurodegenerative diseases. The maintenance in energy production is crucial to face and recover from oxidative damage, and the preservation of different sources of energy production is essential to preserve neuronal function. Fingolimod phosphate is a drug with neuroprotective and antioxidant actions, used in the treatment of multiple sclerosis. This work was performed in a model of oxidative damage on neuronal cell cultures exposed to menadione in the presence or absence of fingolimod phosphate. We studied the mitochondrial function, antioxidant enzymes, protein nitrosylation, and several pathways related with glucose metabolism and glycolytic and pentose phosphate in neuronal cells cultures. Our results showed that menadione produces a decrease in mitochondrial function, an imbalance in antioxidant enzymes, and an increase in nitrosylated proteins with a decrease in glycolysis and glucose-6-phosphate dehydrogenase. All these effects were counteracted when fingolimod phosphate was present in the incubation media. These effects were mediated, at least in part, by the interaction of this drug with its specific S1P receptors. These actions would make this drug a potential tool in the treatment of neurodegenerative processes, either to slow progression or alleviate symptoms.