title: Toxicokinetics of the nerve agent (+/-)-VX in anesthetized and atropinized hairless guinea pigs and marmosets after intravenous and percutaneous administration.
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 > or =10 pg/ml. The ratio of the two enantiomers of VX in blood could be measured at levels > or =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.
authors.affiliation: Division Chemical and Biological Protection, TNO Prins Maurits Laboratory, PO Box 45, 2280 AA, Rijswijk, The Netherlands. schansm@pml.tno.nl
authors.forename: Marcel J
authors.initials: MJ
authors.lastname: van der Schans
authors.forename: Brenda J
authors.initials: BJ
authors.lastname: Lander
authors.forename: Herma
authors.initials: H
authors.lastname: van der Wiel
authors.forename: Jan P
authors.initials: JP
authors.lastname: Langenberg
authors.forename: Hendrik P
authors.initials: HP
authors.lastname: Benschop
mesh_terms: D000110:Acetylcholinesterase / Q000097:blood; D000287:Administration, Topical; D000758:Anesthesia; D000818:Animals; D001285:Atropine / Q000494:pharmacology*; D002144:Callithrix; D002619:Chemical Warfare Agents / Q000493:pharmacokinetics* / Q000633:toxicity*; D002849:Chromatography, Gas; D002851:Chromatography, High Pressure Liquid; D004563:Electrochemistry; D006168:Guinea Pigs; D007275:Injections, Intravenous; D007700:Kinetics; D007928:Lethal Dose 50; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D009946:Organothiophosphorus Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D013237:Stereoisomerism
chemical_list: D000110:Acetylcholinesterase; D001285:Atropine; D002619:Chemical Warfare Agents; D018727:Muscarinic Antagonists; D009946:Organothiophosphorus Compounds; C009680:VX-agent