Quantifying Intranasally Administered Deferoxamine in Rat Brain Tissue with Mass Spectrometry.

Deferoxamine, a metal chelator, has been shown to be neuroprotective in animal models of ischemic stroke, traumatic brain injury and both subarachnoid and intracerebral hemorrhage. Intranasal deferoxamine (IN DFO) has also shown promise as a potential treatment for multiple neurodegenerative diseases, including Parkinson's and Alzheimer's. However, there have been attempts to thoroughly understand the dynamics and pharmacokinetics of IN DFO. We developed a new high-performance liquid-chromatography electrospray-tandem mass spectrometry (HPLC/ESI-MS²) method to quantify the combined total levels of DFO, ferrioxamine (FO; DFO bound to iron) and aluminoxamine (AO; aluminum-bound DFO) in brain tissue using a custom-synthesized deuterated analog (DFO-d₇, Medical Isotopes Inc., Pelham NH) as an internal standard. We applied our method towards understanding the pharmacokinetics of IN DFO delivery to the brain and blood of rats from 15 minutes to four hours after delivery. We found that IN delivery successfully targets DFO to the brain to achieve concentrations of 0.5-15 µM in various brain regions within 15 min, and decreasing though still detectable after 4 hours. Systemic exposure was minimized as assessed by concentration in blood serum. Serum concentrations were 0.02 µM at 15 min and no more than 0.1 µM at later time points. Compared to blood serum, brain region-specific drug exposure (as measured by area-under-curve) ranged from slightly under 10-times exposure in hippocampus to almost 200-times exposure in olfactory bulb with IN DFO delivery. These findings represent a major step towards future method development, pharmacokinetic studies, and clinical trials for this promising therapeutic.