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
Jazyk angličtina Země Spojené státy americké Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
- Klíčová slova
- acetylcholinesterase, cucurbit[n]uril, liquid chromatography, mass spectrometry, oxime, reactivator,
- MeSH
- acetylcholinesterasa metabolismus MeSH
- cholinesterasové inhibitory aplikace a dávkování toxicita MeSH
- enzymatické testy MeSH
- hematoencefalická bariéra metabolismus MeSH
- hmotnostní spektrometrie MeSH
- hydrofobní a hydrofilní interakce MeSH
- imidazoly chemie MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- myši MeSH
- nosiče léků chemie MeSH
- otrava organofosfáty farmakoterapie MeSH
- oximy aplikace a dávkování farmakokinetika MeSH
- plocha pod křivkou MeSH
- přemostěné cyklické sloučeniny chemie MeSH
- pyridinové sloučeniny aplikace a dávkování farmakokinetika MeSH
- reaktivátory cholinesterázy aplikace a dávkování farmakokinetika MeSH
- sarin aplikace a dávkování toxicita MeSH
- vysokoúčinná kapalinová chromatografie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- acetylcholinesterasa MeSH
- asoxime chloride MeSH Prohlížeč
- cholinesterasové inhibitory MeSH
- cucurbit(7)uril MeSH Prohlížeč
- imidazoly MeSH
- nosiče léků MeSH
- oximy MeSH
- přemostěné cyklické sloučeniny MeSH
- pyridinové sloučeniny MeSH
- reaktivátory cholinesterázy 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.
Citace poskytuje Crossref.org
Strategies for enhanced bioavailability of oxime reactivators in the central nervous system
