Back to Search
Start Over
Encapsulation of oxime K027 into cucurbit[7]uril: In vivo evaluation of safety, absorption, brain distribution and reactivation effectiveness.
- Source :
-
Toxicology letters [Toxicol Lett] 2020 Mar 01; Vol. 320, pp. 64-72. Date of Electronic Publication: 2019 Nov 30. - Publication Year :
- 2020
-
Abstract
- Oxime-based acetylcholinesterase reactivators (briefly oximes) regenerate organophosphate-inactivated acetylcholinesterase and restore its function. Poor blood-brain-barrier passage and fast elimination from blood limit their actual use in treatment of patients exposed to organophosphates. Previous in vitro results implicated further testing of cucurbit[7]uril as a delivery vehicle for bisquaternary oximes. The present paper focuses on cell toxicity, in vivo safety and influence of cucurbit[7]uril on oxime pharmacokinetics and pharmacodynamics. Neither the K027 nor the complex caused any cell toxicity, changes in blood biochemistry or hepato- or nephrotoxicity in tested concentrations. The encapsulation of K027 increased and accelerated the blood-brain-barrier penetration. The peripheral oxime exposure also increased, supporting the suggestion that cucurbit[7]uril protects the circulating oxime from rapid renal clearance. Contrary to the comparable in vitro reactivation power of K027 and the encapsulated K027, we failed to confirm this in vivo. In theory, this might result from the non-specific binding of molecules to the cucurbit[7]uril or the interaction of K027 with cucurbit[7]uril being too strong for acetylcholinesterase reactivation. Precise explanation requires additional in silico, in vitro and also in vivo experiments.<br /> (Copyright © 2019 Elsevier B.V. All rights reserved.)
- Subjects :
- A549 Cells
Animals
Brain enzymology
Bridged-Ring Compounds administration & dosage
Bridged-Ring Compounds toxicity
Cell Survival drug effects
Cholinesterase Reactivators administration & dosage
Cholinesterase Reactivators toxicity
Dose-Response Relationship, Drug
Erythrocytes enzymology
Female
GPI-Linked Proteins blood
GPI-Linked Proteins metabolism
Hep G2 Cells
Humans
Imidazoles administration & dosage
Imidazoles toxicity
Injections, Intramuscular
Male
Maximum Tolerated Dose
Mice, Inbred ICR
Oximes administration & dosage
Oximes toxicity
Pyridinium Compounds administration & dosage
Pyridinium Compounds toxicity
Risk Assessment
Tissue Distribution
Acetylcholinesterase blood
Acetylcholinesterase metabolism
Brain drug effects
Bridged-Ring Compounds pharmacokinetics
Cholinesterase Reactivators pharmacokinetics
Erythrocytes drug effects
Imidazoles pharmacokinetics
Oximes pharmacokinetics
Pyridinium Compounds pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 1879-3169
- Volume :
- 320
- Database :
- MEDLINE
- Journal :
- Toxicology letters
- Publication Type :
- Academic Journal
- Accession number :
- 31794810
- Full Text :
- https://doi.org/10.1016/j.toxlet.2019.11.021