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

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Author: Schans, M.J. van der · Lander, B.J. · Wiel, H. van der · Langenberg, J.P. · Benschop, H.P.
Type:article
Date:2003
Institution: Prins Maurits Laboratorium TNO
Source:Toxicology and Applied Pharmacology, 1, 191, 48-62
Identifier: 237224
doi: doi:10.1016/S0041-008X(03)00216-3
Keywords: Biology · Chiral HPLC · Hairless guinea pigs · Intravenous · Marmosets · Percutaneous · Persistence · Stereospecificity · Toxicokinetics · Treatment · Carbamic acid · Oxime · Volatile agent · Anesthesia · Animal experiment · Animal model · Bioavailability · Blood level · Dose response · Enantiomer · Guinea pig · Intoxication · Marmoset · Nonhuman · Primate · Toxicokinetics · Administration, Topical · Anesthesia · Animals · Atropine · Callithrix · Chemical Warfare Agents · Chromatography, Gas · Chromatography, High Pressure Liquid · Electrochemistry · Injections, Intravenous · Kinetics · Lethal Dose 50 · Male · Muscarinic Antagonists · Organothiophosphorus Compounds · Stereoisomerism · Animalia · Cavia · Cavia porcellus · Primates · Sus scrofa · Acetylcholinesterase, 9000-81-1 · Carbamic acid, 463-77-4 · Methylphosphonothioic acid s (2 diisopropylaminoethyl) o ethyl ester, 50782-69-9 · Sarin, 107-44-8 · Soman, 96-64-0 · Acetylcholinesterase, EC 3.1.1.7 · Atropine, 51-55-8 · Chemical warfare agents · Muscarinic antagonists · Organothiophosphorus compounds · VX, 50782-69-9

Abstract

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.