Quantifying Intranasally Administered Deferoxamine in Rat Brain Tissue with Mass Spectrometry

Abstract

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-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 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.

Nrf2 regulates iron-dependent hippocampal synapses and functional connectivity damage in depression

“…The targeted delivery of drugs to the central nervous system (CNS) through IN administration circumvents the blood‒brain barrier (BBB), which minimizes systemic exposure and reduces associated adverse effects. It has been previously demonstrated that intranasal administration increased the targeting of DFO to the brain compared to intravenous delivery [ 39 ]. In our study, DFOM was dissolved in pyrogen-free normal saline solution and administered intranasally three times a week at a dose of 100 mg/kg.…”

Early postoperative complications in patients with acute myocardial infarction during emergency coronary bypassing

“…The long-term prognosis for primary PCI and external CABG is similar, but the average length of hospital stay for PCI is shorter. In addition, a large number of modern clinics do not always have the opportunity to accept a patient urgently for surgery (Fan et al, 2021;Kosyakovsky et al, 2019). Therefore, it is necessary to develop simple clear criteria for selecting patients with acute myocardial infarction for emergency surgical revascularization.…”