Pharmacokinetic study of two acetylcholinesterase reactivators, trimedoxime and newly synthesized oxime K027, in rat plasma

Abstract

K027 [1-(4-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium)-propane dibromide] is a promising new reactivator of organophosphate- or organophosphonate-inhibited acetylcholinesterase (AChE) with low acute toxicity and broad spectrum efficacy. The aim of the present study was to compare the pharmacokinetics of both compounds. Male Wistar rats (body weight = 320 ± 10 g) were administered a single intramuscular dose of K027 (22.07 mg kg(-1)) and an equimolar dose of trimedoxime. Blood was collected at various time intervals until 180 min. Plasma samples were analyzed by reversed-phase HPLC with ultraviolet (UV) detection. The recovery of both oximes from the plasma was approximately 90% and a linear relationship (R(2) > 0.998) was observed between the peak areas and concentrations of calibrated standards in the range 1-100 µg ml(-1). Near-identical plasma profiles were obtained for both compounds. No differences were found in the mean ± SD values of C(max) (18.6 ± 2.5 vs 20.0 ± 6.3 µg ml(-1), P = 0.72) and AUC(0-180min) (2290 ± 304 vs 2269 ± 197 min µg ml(-1), P = 0.84). However, the percentage coefficient of variation of the first-order rate constant of absorption (k(a)) was 3-fold higher (P < 0.01) providing evidence for more erratic absorption of intramuscular trimedoxime as compared with K027. In conclusion, oxime K027 might have superior pK properties that may be translated in its faster absorption and subsequent tissue distribution.

Reversible cholinesterase inhibitors as pretreatment for exposure to organophosphates. A review

“…As with other pyridinium oximes, K‐27 weakly inhibits AChE activity (Lorke, Hasan, Arafat, et al, ), but its principal functional mechanism is AChE reactivation. In vivo, the estimated half‐life of K‐27 in plasma is between 30 minutes (Lorke, Hasan, Arafat, et al, ) and 2 hours (Karasova et al, ), and we have measured a K‐27 plasma level of approximately 300 μ m 30 minutes after injection of 50 μmol K‐27 (Lorke et al, ). It may therefore be that 30 minutes after a 60 μmol K‐27 injection (pretreatment interval), K‐27 levels in the experimental animals are still sufficiently high to reactivate AChE inhibited by subsequent OPC exposure.…”

Translation of in vitro to in vivo pyridinium oxime potential in tabun poisoning / Translacija učinkovitosti piridinijevih oksima kod trovanja tabunom iz in vitro sustava u in vivo primjenu

“…Figure 1 summarises K048 distribution and elimination across tissues. As a positively charged compound, K048 is quickly eliminated from the organism (28)(29)(30). In our study the entire dose (60 mg kg -1 body weight) was eliminated within a few hours from i.p.…”

HPLC determination of K027 in the body of pregnant mice

“…1), a bispyridinium monoaldoxime [7]. Considering lipophilicity of these compounds, K027, K048, and K203 show the upmost negative log P as well as the largest total polar surface area (TPSA) values [14][15][16]. Tekes et al [17,18] determined the level of K027 in serum, the brain, cerebrospinal fluid, and urine following i.m.…”