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

K-oximes have recently been developed in the search for efficacious broad-band reactivators of acetylcholinesterase (ACNE) 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 ACNE inhibitory activity of oximes, as reflected by their in vitro IC50, is strongly correlated with their LD50 (rat): oximes with a high IC50 (K-27, K-48, pralidoxime and obidoxime) also show a high LD50 and are thus relatively non-toxic, whereas oximes K-105, K-108 and K-113 have a low IC50, a low LD50 and are far more toxic. The IC50 is also correlated with the in vivo capacity to protect from paraoxon-induced mortality: oximes with a higher IC50 reduce the relative risk of death more. In contrast, the protective ability as assessed in vitro by the slope of the IC50 shift (tan alpha), 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 tan alpha value (around 2) than K-110 and K-113 (tan alpha 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 IC50 and with their LD50 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 IC50 testing for in vivo toxicity and the limited practical significance of in vitro assessment of protective potency. Copyright (C) 2009 John Wiley & Sons, Ltd.