Toxicokinetics of the nerve agent (±)-VX in anesthetized and atropinized hairless guinea pigs and marmosets after intravenous and percutaneous administration

In continuation of our investigations on the toxicokinetics of the volatile nerve agents C(±)P(±)-soman and (±)-sarin, we now report on the toxicokinetics of the rather nonvolatile agent (±)-VX. A validated method was developed to determine blood levels of (±)-VX by means of achiral gas chromatography at blood levels ≥10 pg/ml. The ratio of the two enantiomers of VX in blood could be measured at levels ≥1 ng/ml by using chiral HPLC in combination with off-line gas chromatographic analysis. In order to obtain basic information on the toxicokinetics of (±)-VX, i.e., under conditions of 100% bioavailability, the blood levels of this agent were measured in hairless guinea pigs at iv doses corresponding with 1 and 2 LD50. The derived AUCs indicate a reasonable linearity of the toxicokinetics with dose. Also, the toxicokinetics in marmoset primates was studied at an absolute iv dose corresponding with 1 LD50 in the hairless guinea pig which led to approximately the same levels of (±)-VX in blood as observed at 2 LD50 in the hairless guinea pig. Finally, the toxicokinetics of (±)-VX were measured in hairless guinea pigs via the most relevant porte d’ entrée for this agent, which is the percutaneous route at a dose corresponding with 1 LD50 (pc). Large variations were observed between individual animals in the rate of penetration of (±)-VX and in concomitant progression of AChE inhibition in blood of these animals. Blood levels of (±)-VX increased gradually over a 6-h period of time. After a 7-h penetration period, the total AUC corresponded with 2.5% bioavailability relative to iv administration. In contrast with the G-agents C(±)P(±)-soman and (±)-sarin, stereospecificity in the sequestration of the two enantiomers of (±)-VX is not a prominent phenomenon. It appears that (±)-VX is substantially more persistent in vivo than the two G-agents. This persistence may undermine the efficacy of pretreatment with carbamates of percutaneous intoxication in particular due to gradual replacement of carbamate on AChE by (±)-VX, whereas classical treatment of intoxication with oximes is hampered by the short persistence of oximes relative to the agent.