Minireview: does in‐vitro testing of oximes help predict their in‐vivo action after paraoxon exposure?

Abstract

K-oximes have recently been developed in the search for efficacious broad-band reactivators of acetylcholinesterase (AChE) inhibited by organophosphorus compounds (OPC). Before clinical use, their toxicity and efficacy need to be assessed, and there is clear demand for simple in vitro tests that can predict in vivo performance. This article summarizes our in vitro data obtained for conventional and experimental oximes in human and rat blood exposed to the OPC paraoxon and correlates them with our in vivo results. The intrinsic AChE inhibitory activity of oximes, as reflected by their in vitro IC(50), is strongly correlated with their LD(50) (rat): oximes with a high IC(50) (K-27, K-48, pralidoxime and obidoxime) also show a high LD(50) and are thus relatively non-toxic, whereas oximes K-105, K-108 and K-113 have a low IC(50), a low LD(50) and are far more toxic. The IC(50) is also correlated with the in vivo capacity to protect from paraoxon-induced mortality: oximes with a higher IC(50) reduce the relative risk of death more. In contrast, the protective ability as assessed in vitro by the slope of the IC(50) shift (tanalpha), is not correlated with in vivo protection from paraoxon-induced mortality: the best in vivo protectors (K-27 and K-48) show a much lower tanalpha value (around 2) than K-110 and K-113 (tanalpha around 10), which hardly reduce the relative risk of death after paraoxon exposure. The partition coefficient logP of the individual oximes is inversely correlated with their IC(50) and with their LD(50) and is therefore an indicator of toxicity: strongly hydrophilic oximes tend to be less toxic than less hydrophilic ones. These data highlight the good predictive value of in vitro IC(50) testing for in vivo toxicity and the limited practical significance of in vitro assessment of protective potency.

Comparison of the Ability of Pyridinium Aldoximes to Reactivate Human Red Blood Cell Acetylcholinesterases Inhibited by ethyl- and methyl-paraoxon

“…Chemical structure and IC50 of organophosphate cholinesterase inhibitors assessed for human red blood cell (*, **, ***), bovine red blood cell (****) or mouse cultured neuronal (*****) acetylcholinesterase. * [56], ** [57], *** [58], **** [59], ***** [60]. [2].…”

“…When correlating in vitro and in vivo data, it becomes well obvious that neither in the case of paraoxon exposure [56] nor in the case of DFP exposure [68], the tan values of the individual oximes determined in vitro in the RBC system are correlated with the cumulative relative risk of death after OPIChE plus oxime exposure in vivo. This implies that in vitro determination of the slope of the IC 50 shift induced by addition of oximes has very limited predictive value for their in vivo efficacy to reduce OPIChE-induced mortality.…”

“…Hence rodentderived data can only partially be extrapolated to higher species. We therefore also determined the IC 50 and the slope of the IC 50 shift (tan ) using blood of rat origin [56]. However, no correlation between in vivo efficacy to reduce OPIChE-induced mortality and tan values was observed in the rat blood system either.…”

In Silico Studies in Probing the Role of Kinetic and Structural Effects of Different Drugs for the Reactivation of Tabun-Inhibited AChE

“…For 2-PAM, the BBB penetration (striatal extracellular/blood concentration ratio) was estimated to be approximately only 10% using the in vivo rat brain microdialysis technique [20]. The diffusion of oximes into the BBB depends upon their lipid solubility and is inversely proportional to their degree of ionization [51]. To examine the lipophilicity of the drugs and their penetration to the blood-brain barrier, LogP values were calculated [21], [52].…”

Oxime treatment for organophosphorus compound exposure: Getting it (into the brain) might not be that good for you, after all

“…After correlating in vivo toxicity of various oximes with different in vitro parameters (Lorke and Petroianu, 2009), our own experimental studies indicate that a negative log P (strong hydrophilicity) is a good predictor for low oxime toxicity (as assessed by survival). In addition, oximes with very negative log P (strong hydrophilicity) were significantly more efficacious in reducing DFP-induced mortality than more lipophilic ones.…”