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
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2021 |
|---|---|
| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:18 |
|---|---|
| Enthalten in: |
Molecular pharmaceutics - 18(2021), 6 vom: 07. Juni, Seite 2416-2427 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Andrýs, Rudolf [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 17.12.2021 Date Revised 17.12.2021 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1021/acs.molpharmaceut.1c00257 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM325687749 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM325687749 | ||
| 003 | DE-627 | ||
| 005 | 20231225192951.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2021 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1021/acs.molpharmaceut.1c00257 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1085.xml |
| 035 | |a (DE-627)NLM325687749 | ||
| 035 | |a (NLM)34019427 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Andrýs, Rudolf |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Effect of Oxime Encapsulation on Acetylcholinesterase Reactivation |b Pharmacokinetic Study of the Asoxime-Cucurbit[7]uril Complex in Mice Using Hydrophilic Interaction Liquid Chromatography-Mass Spectrometry |
| 264 | 1 | |c 2021 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 17.12.2021 | ||
| 500 | |a Date Revised 17.12.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a acetylcholinesterase | |
| 650 | 4 | |a cucurbit[n]uril | |
| 650 | 4 | |a liquid chromatography | |
| 650 | 4 | |a mass spectrometry | |
| 650 | 4 | |a oxime | |
| 650 | 4 | |a reactivator | |
| 650 | 7 | |a Bridged-Ring Compounds |2 NLM | |
| 650 | 7 | |a Cholinesterase Inhibitors |2 NLM | |
| 650 | 7 | |a Cholinesterase Reactivators |2 NLM | |
| 650 | 7 | |a Drug Carriers |2 NLM | |
| 650 | 7 | |a Imidazoles |2 NLM | |
| 650 | 7 | |a Oximes |2 NLM | |
| 650 | 7 | |a Pyridinium Compounds |2 NLM | |
| 650 | 7 | |a cucurbit(7)uril |2 NLM | |
| 650 | 7 | |a Sarin |2 NLM | |
| 650 | 7 | |a B4XG72QGFM |2 NLM | |
| 650 | 7 | |a Acetylcholinesterase |2 NLM | |
| 650 | 7 | |a EC 3.1.1.7 |2 NLM | |
| 650 | 7 | |a asoxime chloride |2 NLM | |
| 650 | 7 | |a HUV88P6SJS |2 NLM | |
| 700 | 1 | |a Klusoňová, Aneta |e verfasserin |4 aut | |
| 700 | 1 | |a Lísa, Miroslav |e verfasserin |4 aut | |
| 700 | 1 | |a Kassa, Jiří |e verfasserin |4 aut | |
| 700 | 1 | |a Karasová, Jana Žd'árová |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Molecular pharmaceutics |d 2004 |g 18(2021), 6 vom: 07. Juni, Seite 2416-2427 |w (DE-627)NLM154556807 |x 1543-8392 |7 nnns |
| 773 | 1 | 8 | |g volume:18 |g year:2021 |g number:6 |g day:07 |g month:06 |g pages:2416-2427 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1021/acs.molpharmaceut.1c00257 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 18 |j 2021 |e 6 |b 07 |c 06 |h 2416-2427 | ||