title: In vitro and in vivo toxicological studies of V nerve agents: molecular and stereoselective aspects.
abstract: In vitro inhibition data of cholinesterases (ChEs) and reactivation with HI 6 are presented for separated VX and VR enantiomers with high purity (enantiomer excess >99.999%). Inhibition rate constants for (-)-VR were fourfold higher than for (-)-VX. Marked higher stereoselectivity of ChEs inhibition was observed for VR compared with VX enantiomers. Low/no reactivation was determined for respective (+)-enantiomers. Results were related to orientation of (-)- and (+)-enantiomers in ChEs active sites. In vivo in swine, absorption rate constants were practically identical for VX and VR enantiomers after percutaneous application of 3xLD₅₀ underlining relevance of amine group and postulated equilibria shifts between charged, uncharged, open and cyclic form (skin depot). In vivo toxicokinetics of VX and VR enantiomers differed markedly after 4h. Elimination of VX was much slower compared with VR. Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition in vivo differed for VX and VR. In vivo spontaneous reactivation was not observed for VX-inhibited AChE while VR-inhibited AChE was much faster spontaneously reactivated than expected and AChE inhibition by VR was slower than expected. Progredient BChE inhibition was detected after VX application while VR inhibited BChE weakly. Possible explanation may be impact of the agents on hemodynamics and different metabolisms. Thus, due to increase of the V agents' blood concentration after atropine administration (depot release) the present standard therapy should be thoroughly reconsidered.
authors.affiliation: Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstrasse 11, 80937 Munich, Germany. Electronic address: georgreiter@bundeswehr.org.
authors.forename: Georg
authors.initials: G
authors.lastname: Reiter
authors.affiliation: Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstrasse 11, 80937 Munich, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Müller
authors.affiliation: Defence Research & Development Canada - Suffield, P.O. Box 4000 Stn MaIn, Medicine Hat, Alberta T1A 8K6 Canada.
authors.forename: Ira
authors.initials: I
authors.lastname: Hill
authors.affiliation: Defence Research & Development Canada - Suffield, P.O. Box 4000 Stn MaIn, Medicine Hat, Alberta T1A 8K6 Canada.
authors.forename: Kendal
authors.initials: K
authors.lastname: Weatherby
authors.affiliation: Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstrasse 11, 80937 Munich, Germany.
authors.forename: Horst
authors.initials: H
authors.lastname: Thiermann
authors.affiliation: Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstrasse 11, 80937 Munich, Germany.
authors.forename: Franz
authors.initials: F
authors.lastname: Worek
authors.affiliation: Defence Research & Development Canada - Suffield, P.O. Box 4000 Stn MaIn, Medicine Hat, Alberta T1A 8K6 Canada.
authors.forename: John
authors.initials: J
authors.lastname: Mikler
mesh_terms: D000287:Administration, Topical; D000818:Animals; D002619:Chemical Warfare Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D008297:Male; D009946:Organothiophosphorus Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D012869:Skin Absorption; D013237:Stereoisomerism; D013552:Swine
chemical_list: D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D009946:Organothiophosphorus Compounds; C009680:VX-agent; C451779:S-(N,N-diethylaminoethyl) isobutyl methylphosphothiolate
keywords: Acetylcholinesterase; Enantiomers; Russian VX; Toxicokinetics; VR; VX