AbstractMono- and bis-pyridinium quaternary aldoximes (K-oximes) have long been employed as cholinesterase reactivator components of antidotes against lethal cholinesterase-inhibiting organophosphorous chemicals. Their positive charge poses difficulties in their chromatographic analysis, resulting in the publication of different approaches for each K-oxime. A multiplexed method is presented for the rapid quantitation of 10 K-oximes in blood with its utility demonstrated in vivo. Liquid chromatography with absorbance detection was employed. Reversed-phase separation was achieved on a highly nonpolar stationary phase. Method validation was based on the respective guideline of the European Medicines Agency. Times to peak concentrations and 120-min areas under the time–concentration curves were determined in rats following intraperitoneal administration. Adequate retention and separation of K-oximes with acceptable peak shapes in short isocratic runs was achieved by adjusting ionic strength, organic content and the concentration of the ion-pairing agent of the mobile phase. Chromatographic properties were governed by optimizing the concentration of dissolved ions. Accurate adjustment of the organic content was indispensable for avoiding peak drifting and splitting. Dose-adjusted exposure to K-347 and K-868 was exceptionally low, while exposure to K-48 was the highest. The method is suitable for screening systemic exposure to various K-oximes and can be extended.
Our aim was to find chlorine-substituted antidotes against organophosphate poisoning and compare their pharmacokinetics to their parent compound, K-203. White male Wistar rats were intramuscularly injected with K-203, K-867 or K-870. Serum, brain, kidneys, liver, lung, eyes, and testes tissues were taken after 5, 15, 30, 60, and 120 min and analyzed using reversed-phase high-performance liquid chromatography. K-203, K-867, or K-870 was present in every tissue that was analyzed, including the serum, the eyes, testes, liver, kidneys, lungs, and the brain. The serum levels of K-867 and K-870 (chlorine-substituted derivatives of K-203) were nearly constant between 15 and 30 min, while their parent compound (K-203) showed peak level at 15 min after the administration of 30 µmol/rat. Neither K-203, nor K-867 or K-870 were toxic at a dose of 100 µmol/200 g in rats. Chlorine-substitution of K-867 and K-870 produced limited absorbance and distribution compared to their parent compound, K203.
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