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Determination of K869, a Novel Oxime Reactivator of Acetylcholinesterase, in Rat Body Fluids and Tissues by Liquid-Chromatography Methods: Pharmacokinetic Study

N. Vanova, A. Hojna, J. Pejchal, D. Herman, D. Malinak, E. Prchalova, K. Musilek, JZ. Karasova

. 2021 ; 110 (4) : 1842-1852. [pub] 20210203

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc21018930

Oxime reactivators of acetylcholinesterase (AChE) represent an integral part of standard antidote treatment of organophosphate poisoning. Oxime K869 is a novel bisquaternary non-symmetric pyridinium aldoxime with two pyridinium rings connected by a tetramethylene bridge where two chlorines modify the pyridinium ring bearing the oxime moiety. Based on in vitro assays, K869 is a potent AChE and butyrylcholinesterase (BChE) reactivator. For the investigation of the basic pharmacokinetic properties of K869 after its intramuscular application, new HPLC-UV and LC-MS/MS methods were developed and validated for its determination in rat body fluids and tissues. In this study, the SPE procedure for sample pretreatment was optimized as an alternative to routine protein precipitation widely used in oxime pharmacokinetics studies. K869 oxime is quickly absorbed into the central compartment reaching its maximum in plasma (39 ± 4 μg/mL) between 15 and 20 min. The majority of K869 was eliminated by kidneys via urine when compared with biliary excretion. However, only a limited amount of K869 (65 ± 4 ng/g of brain tissue) was found in the brain 30 min after oxime administration. Regarding the brain/plasma ratio calculated (less than 1%), the penetration of K869 into the brain did not exceed conventionally used oximes.

Citace poskytuje Crossref.org

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$a Vanova, Nela $u Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Kralove, Charles University, Czech Republic. Electronic address: vanovan@faf.cuni.cz
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$a Oxime reactivators of acetylcholinesterase (AChE) represent an integral part of standard antidote treatment of organophosphate poisoning. Oxime K869 is a novel bisquaternary non-symmetric pyridinium aldoxime with two pyridinium rings connected by a tetramethylene bridge where two chlorines modify the pyridinium ring bearing the oxime moiety. Based on in vitro assays, K869 is a potent AChE and butyrylcholinesterase (BChE) reactivator. For the investigation of the basic pharmacokinetic properties of K869 after its intramuscular application, new HPLC-UV and LC-MS/MS methods were developed and validated for its determination in rat body fluids and tissues. In this study, the SPE procedure for sample pretreatment was optimized as an alternative to routine protein precipitation widely used in oxime pharmacokinetics studies. K869 oxime is quickly absorbed into the central compartment reaching its maximum in plasma (39 ± 4 μg/mL) between 15 and 20 min. The majority of K869 was eliminated by kidneys via urine when compared with biliary excretion. However, only a limited amount of K869 (65 ± 4 ng/g of brain tissue) was found in the brain 30 min after oxime administration. Regarding the brain/plasma ratio calculated (less than 1%), the penetration of K869 into the brain did not exceed conventionally used oximes.
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$a Hojna, Anna $u Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Kralove, Charles University, Czech Republic
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$a Malinak, David $u Faculty of Science, Department of Chemistry, University of Hradec Kralove, Hradec Kralove, Czech Republic; University Hospital Hradec Kralove, Biomedical Research Centre, Hradec Kralove, Czech Republic
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$a Musilek, Kamil $u Faculty of Science, Department of Chemistry, University of Hradec Kralove, Hradec Kralove, Czech Republic; University Hospital Hradec Kralove, Biomedical Research Centre, Hradec Kralove, Czech Republic
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$a Karasova, Jana Zdarova $u Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defense, Czech Republic; University Hospital Hradec Kralove, Biomedical Research Centre, Hradec Kralove, Czech Republic
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