Pharmacokinetic profile of promising acetylcholinesterase reactivators K027 and K203 in experimental pigs
Language English Country Netherlands Media print-electronic
Document type Journal Article
PubMed
28343895
DOI
10.1016/j.toxlet.2017.03.017
PII: S0378-4274(17)30119-4
Knihovny.cz E-resources
- Keywords
- Acetylcholinesterase, K027, K203, Nerve agents, Oxime, Pharmacokinetics, Pigs,
- MeSH
- Acetylcholinesterase metabolism MeSH
- Administration, Oral MeSH
- Injections, Intramuscular MeSH
- Organ Specificity MeSH
- Oximes administration & dosage blood pharmacokinetics MeSH
- Area Under Curve MeSH
- Pyridinium Compounds administration & dosage blood pharmacokinetics MeSH
- Cholinesterase Reactivators administration & dosage blood pharmacokinetics MeSH
- Sus scrofa MeSH
- Tissue Distribution MeSH
- Chromatography, High Pressure Liquid MeSH
- Animals MeSH
- Check Tag
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- 1-(4-carbamoylpyridinium)-4-(4-hydroxyiminomethylpyridinium)but-2-ene MeSH Browser
- 1-(4-hydroxyiminomethylpyridinium)-3-(carbamoylpyridinium) propane dibromide MeSH Browser
- Acetylcholinesterase MeSH
- Oximes MeSH
- Pyridinium Compounds MeSH
- Cholinesterase Reactivators MeSH
Standard treatment of organophosphorus compounds (OPs) poisoning includes administration of an anti-muscarinic (atropine), anticonvulsive (diazepam) and acetylcholinesterase reactivator (oxime). From a wide group of newly synthesized oximes, oxime K027 and oxime K203 seem to be perspective compounds in some specific OPs intoxication. The available in vitro and in vivo preclinical data indicate that both oximes may be considered for potential human use. The main aim of this study was to establish plasmatic concentration curves of both oximes after intramuscular (i.m.) and intragastric (i.g.) application with subsequent pharmacokinetic analysis and study distribution after (i.m.) application on a non-rodent animal model (experimental pigs; 1500mg/animal). According to the results, both oximes had similar Cmax (K027: 106±19μg/mL and K203: 111±8μg/mL) in Tmax 19±5min, respectively, in 22±3min. Bioavailability of oxime K027 calculated as AUCtotal (8389±1024minμg/mL) was halved compared to oxime K203 (16938±795minμg/mL). The highest concentration from peripheral tissues was found in the kidney and lung, but the brain concentrations stay very low, the plasma/brain ratio being approximately 1%. The applied doses were derived from the recommendation where it is possible to use three autoinjectors to save human life. The results provide us with knowledge about the pharmacokinetics and distribution of these new oximes and may help us to better estimate the human pharmacokinetic profile.
Biomedical Research Center University Hospital Hradec Kralove Czech Republic
Department of Military Surgery Faculty of Military Health Sciences Hradec Kralove Czech Republic
References provided by Crossref.org
Brominated oxime nucleophiles are efficiently reactivating cholinesterases inhibited by nerve agents
Acute Toxic Injuries of Rat's Visceral Tissues Induced by Different Oximes
