Toxicokinetics of the nerve agent (±)-VX in anesthetized and atropinized hairless guinea pigs and marmosets after intravenous and percutaneous administration
van der Schans, M.J.
van der Wiel, H.
Prins Maurits Laboratorium TNO
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. © 2003 Elsevier Science (USA). All rights reserved.
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Hairless guinea pigs
Chemical Warfare Agents
Chromatography, High Pressure Liquid
Lethal Dose 50
Carbamic acid, 463-77-4
Methylphosphonothioic acid s (2 diisopropylaminoethyl) o ethyl ester, 50782-69-9
Acetylcholinesterase, EC 126.96.36.199
Chemical warfare agents
Toxicology and Applied Pharmacology, 191 (1), 48-62