Toxicokinetics of O-Ethyl S-(2-Diisopropylaminoethyl) Methylphosphonothioate ((+) - VX) in Hairless Guinea Pigs and Marmosets - Identification of Metabolic Pathways

摘要

The toxicokinetics of (+/-)-VX and its metabolites are studied in male hairless guinea pigs for the intravenous (i.v.) and percutaneous (p.c.) routes, and in marmosets for the i.v. route, in order to provide a quantitative basis for pretreatment and therapy of intoxications with this nerve agent. In this report the results obtained in the first two years of the 3-year contract period are presented. An alternative procedure for the quantification of (+/-)- VX using gas chromatography with NP-detection was developed. The detection limit was 1 pg of (+/-)-VX. The ratio between the two enantiomers of (+/-)-VX was determined with chiral normal phase HPLC and electrochemical detection. The toxicokinetics of (+/-)-VX after administration of (+/-)-VX corresponding with a dose of 2 LD50 could be described with a tri-exponential equation with a very rapid first distribution and a very slow elimination phase. A significant deviation from the initial ratio between the two enantiomers could not be observed after administration of (+/-)-VX corresponding with a dose of 2 LD50. An in vitro study to the formation of metabolites, where (+/-)-VX was incubated in liver homogenate of hairless guinea pigs, revealed that the potential metabolites, desethyl-VX and the N-oxide of VX could not be detected. However, EMPA was formed and could be detected in vitro and in vivo.