Many organophosphorous chemical warfare nerve agents have an asymmetric phosphorous atom such that synthesis of these agents results in at least two stereoisomers, designated P(+) and P(-). Although in vitro studies have demonstrated that the P(-)-isomers of these agents are several orders of magnitude more potent inhibitors of acetylcholinesterase than are the P(+)-isomers, only a few in vivo studies have been conducted with optically pure stereoisomers. By subcutaneously exposing mice to each of the stereoisomers of sarin, soman, tabun, and VX, it was determined that the median lethal dose (LD50) values of the P(-)-isomers of these agents were approximately half that of the racemic mixture. However, mice are notthe ideal animal model for studying the toxicity associated with nerve agent exposure because they have relatively high levels of carboxylesterase activity. Thus, studies wereconducted to determine whether the individual stereoisomers of chemical warfare agents have different toxic responses in guinea pigs and to characterize the pharmacokinetics of the individual stereoisomers and their racemic mixtures. This presentation details the results of the gas chromatography-tandem mass spectrometry (GC-MS/MS) analyses of blood to quantify the amounts of O-ethyl methylphosphonofluoridate (VX-G) present from intravenous exposure to P(+) VX, P(-) VX, and a racemic mixture of VX. By applying the GC-MS/MS methos described here, a quantifiable amount of toxicant (in this case VX) can be measured in the blood (as VX-G) as a function of time.

Pharmacokinetics of the stereoisomers of VX in guinea pigs following intravenous exposure

255th National Meeting (2018)

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