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 (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.
Lorke
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DE
Department of Anatomy, FMHS, UAE University, Al Ain, UAE.
Petroianu
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GA
D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity*; D002801:Cholinesterase Reactivators / Q000737:chemistry / Q000494:pharmacology*; D004336:Drug Antagonism; D006801:Humans; D020128:Inhibitory Concentration 50; D007928:Lethal Dose 50; D015394:Molecular Structure; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000494:pharmacology*; D010091:Oximes / Q000737:chemistry / Q000494:pharmacology*; D010261:Paraoxon / Q000633:toxicity*; D021281:Quantitative Structure-Activity Relationship; D051381:Rats
D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D009943:Organophosphorus Compounds; D010091:Oximes; D000110:Acetylcholinesterase; D010261:Paraoxon