Toxicokinetics of O-EthylS- (2-Diisopropylaminoethyl) Methylphosphonothioate ((+) - VX) in Rats, Hairless Guinea Pigs and Marmosets - Identifications of Metabolic Pathways

摘要

Methodology for the quantitative analysis of (j)-VX and 0-ethyl methylphosphonic acid was developed. Moreover a chiral HPLC method was developed where the ratio of the enantiomers of (+/-)-VX could be determined in biological samples. The toxicokinetics of (+/-)-VX and its metabolites were 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. It was found that (+/-)-VX is very persistent after i.v. administration compared to C(+/-)P(+/-)-soman. Even at 6 h after administration (+/-) VX was still present at toxicologically relevant levels in blood of the marmoset and hairless guinea pig after receiving a dose of 28 microng/kg and 56 microng/kg resp. Detoxification of (+/-)-VX proceeds slower in the marmoset than in the hairless guinea pig. There was hardly any stereospecificity observed in the elimination of (i)-VX in vivo. Stereospecific elimination of (j)-VX was observed in in vitro experiments, where (i)-VX was incubated in plasma and liver homogenate from hairless guinea pig, marmoset and man. For further metabolic studies, S(35)-(i)- VX and 14CH3-P-(+/-)-VX were synthesized and were used for in vitro experiments. Labeled (j)-VX was incubated in liver homogenate and plasma from the forementioned species. Formation of the presumed toxic 0-hydrogen S-(2- diisopropylaminoethyl) methylphosphonothioate (desethyl-VX) was observed in plasma samples from all three species but not in liver homogenate. The leaving group containing sulfur transformed into a variety of metabolites and was found to bind to proteins.