| Autor: |
Kosyakovsky J; HealthPartners Neuroscience Center , HealthPartners Institute , Saint Paul , Minnesota 55130 , United States., Witthuhn BA; Department of Biochemistry, Molecular Biology and Biophysics , University of Minnesota , Minneapolis , Minnesota 55108 , United States., Svitak AL; HealthPartners Neuroscience Center , HealthPartners Institute , Saint Paul , Minnesota 55130 , United States., Frey WH 2nd; HealthPartners Neuroscience Center , HealthPartners Institute , Saint Paul , Minnesota 55130 , United States., Hanson LR; HealthPartners Neuroscience Center , HealthPartners Institute , Saint Paul , Minnesota 55130 , United States., Fine JM; HealthPartners Neuroscience Center , HealthPartners Institute , Saint Paul , Minnesota 55130 , United States. |
| Abstrakt: |
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 no 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-MS 2 ) 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 analogue (DFO- d 7 , Medical Isotopes Inc., Pelham NH) as an internal standard. We applied our method toward understanding the pharmacokinetics of IN DFO delivery to the brain and blood of rats from 15 min to 4 h 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 h. 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 the curve) ranged from slightly under 10 times exposure in the hippocampus to almost 200 times exposure in the olfactory bulb with IN DFO delivery. These findings represent a major step toward future method development, pharmacokinetic studies, and clinical trials for this promising therapeutic. |
