Effect of Oxime Encapsulation on Acetylcholinesterase Reactivation: Pharmacokinetic Study of the Asoxime-Cucurbit[7]uril Complex in Mice Using Hydrophilic Interaction Liquid Chromatography-Mass Spectrometry
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
- Keywords
- acetylcholinesterase, cucurbit[n]uril, liquid chromatography, mass spectrometry, oxime, reactivator,
- MeSH
- Acetylcholinesterase metabolism MeSH
- Cholinesterase Inhibitors administration & dosage toxicity MeSH
- Enzyme Assays MeSH
- Blood-Brain Barrier metabolism MeSH
- Mass Spectrometry MeSH
- Hydrophobic and Hydrophilic Interactions MeSH
- Imidazoles chemistry MeSH
- Humans MeSH
- Disease Models, Animal MeSH
- Mice MeSH
- Drug Carriers chemistry MeSH
- Organophosphate Poisoning drug therapy MeSH
- Oximes administration & dosage pharmacokinetics MeSH
- Area Under Curve MeSH
- Bridged-Ring Compounds chemistry MeSH
- Pyridinium Compounds administration & dosage pharmacokinetics MeSH
- Cholinesterase Reactivators administration & dosage pharmacokinetics MeSH
- Sarin administration & dosage toxicity MeSH
- Chromatography, High Pressure Liquid MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Acetylcholinesterase MeSH
- asoxime chloride MeSH Browser
- Cholinesterase Inhibitors MeSH
- cucurbit(7)uril MeSH Browser
- Imidazoles MeSH
- Drug Carriers MeSH
- Oximes MeSH
- Bridged-Ring Compounds MeSH
- Pyridinium Compounds MeSH
- Cholinesterase Reactivators MeSH
- Sarin MeSH
Oxime-based molecules are used for the treatment of patients to reactivate acetylcholinesterase (AChE) function after organophosphate intoxication. However, their efficacy is limited by low penetration through the blood-brain barrier and fast elimination. In this work, the cucurbit[7]uril (CB[7]) carrier was used for the encapsulation of the clinical agent asoxime to enhance brain bioavailability and the treatment window. We present a pharmacokinetic study of asoxime and the asoxime-CB[7] complex in an in vivo mouse model. Ultrahigh-performance liquid chromatography with electrospray ionization-mass spectrometry detection was developed to determine asoxime and CB[7] in biological fluids and tissues after thorough optimization of chromatographic conditions. The dihydroxypropane-silica stationary phase using hydrophilic interaction liquid chromatography conditions provided the best chromatographic performance. The final method was validated and applied for the pharmacokinetic study of mouse plasma, urine, bile, liver, kidney, and brain samples at different times after administration of asoxime and the asoxime-CB[7] complex. The results showed a greater than 3-fold increase in the area under the curve (AUC) in the brain for asoxime administered as a complex with CB[7] relative to that for the administration of asoxime alone. The effectiveness of the treatment strategy was evaluated using a reactivation study and a functional observatory battery. Protection of brain AChE activity is crucial for saving human lives or reducing the consequences of poisoning. The asoxime administered as a complex increased the brain activity by approximately 30% compared to that with atropine alone. CB[7] coadministration improved the AChE activity by 11%, which agrees with the higher asoxime AUC assessed in the pharmacokinetic study.
References provided by Crossref.org
Strategies for enhanced bioavailability of oxime reactivators in the central nervous system
