Pharmacokinetic profile of promising acetylcholinesterase reactivators K027 and K203 in experimental pigs

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F60162694%3AG44__%2F17%3A43875746" target="_blank" >RIV/60162694:G44__/17:43875746 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216208:11150/17:10359332 RIV/00179906:_____/17:10359332

Výsledek na webu

<a href="http://www.sciencedirect.com/science/article/pii/S0378427417301194#" target="_blank" >http://www.sciencedirect.com/science/article/pii/S0378427417301194#</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.toxlet.2017.03.017" target="_blank" >10.1016/j.toxlet.2017.03.017</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Pharmacokinetic profile of promising acetylcholinesterase reactivators K027 and K203 in experimental pigs

Popis výsledku v původním jazyce

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; 1500 mg/animal). According to the results, both oximes had similar C-max (K027: 106 +/- 19 mu g/mL and K203: 111 +/- 8 mu g/mL) in T-max 19 +/- 5 min, respectively, in 22 +/- 3 min. Bioavailability of oxime K027 calculated as AUC(total) (8389 +/- 1024 min mu g/mL) was halved compared to oxime K203 (16938 +/- 795 min mu g/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.

Název v anglickém jazyce

Pharmacokinetic profile of promising acetylcholinesterase reactivators K027 and K203 in experimental pigs

Popis výsledku anglicky

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; 1500 mg/animal). According to the results, both oximes had similar C-max (K027: 106 +/- 19 mu g/mL and K203: 111 +/- 8 mu g/mL) in T-max 19 +/- 5 min, respectively, in 22 +/- 3 min. Bioavailability of oxime K027 calculated as AUC(total) (8389 +/- 1024 min mu g/mL) was halved compared to oxime K203 (16938 +/- 795 min mu g/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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30108 - Toxicology

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2017

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Toxicology Letters

ISSN

0378-4274

e-ISSN

—

Svazek periodika

273

Číslo periodika v rámci svazku

May

Stát vydavatele periodika

IE - Irsko

Počet stran výsledku

6

Strana od-do

20-25

Kód UT WoS článku

000400459600003

EID výsledku v databázi Scopus

2-s2.0-85016417942