Toxicokinetics of tabun enantiomers in anaesthetized swine after intravenous tabun administration.
In the present study, we report the first in vivo toxicokinetic study of tabun (O-ethyl-N,N-dimethylphosphoramidocyanidate). The toxicokinetics of the enantiomers of tabun were investigated in anesthetized swine after intravenous administration of 3xLD(50) (161.4mug/kg) tabun. Blood samples were taken for gas chromatographic-mass spectrometric determination of the tabun enantiomers and for measurement of the activity of red blood cell acetylcholinesterase (AChE) and plasma butyrylcholinesterase (BChE). The tabun enantiomers could be quantified in swine blood to a minimum concentration of 3.0pg/ml (18.5pM) and could be detected to a minimum concentration of 1.0pg/ml (6.2pM). The concentration-time profiles of both tabun enantiomers were best described by a bi-exponential equation. The elimination of (+)-tabun and (-)-tabun were comparable in the initial phase. In the terminal phase a remarkable difference was found, with terminal half lives of 11.5min for (+)-tabun and 23.1min for (-)-tabun. (+)-Tabun showed a markedly longer persistence in vivo than (+)-enantiomers of other G-type nerve agents and could be detected in all swine at least up to 30min post-injection, (-)-tabun at least up to 90min post-injection. These results demonstrate a rather rapid elimination of tabun enantiomers in vivo and may provide a toxicokinetic basis for the further development and optimization of medical countermeasures against this nerve agent.
Tenberken
O
O
Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstrasse 11, 80937 Munich, Germany.
Mikler
J
J
Hill
I
I
Weatherby
K
K
Thiermann
H
H
Worek
F
F
Reiter
G
G
D000110:Acetylcholinesterase / Q000097:blood / Q000378:metabolism; D000769:Anesthesia, Inhalation; D000818:Animals; D002091:Butyrylcholinesterase / Q000097:blood / Q000378:metabolism; D002619:Chemical Warfare Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity*; D008401:Gas Chromatography-Mass Spectrometry; D006207:Half-Life; D007275:Injections, Intravenous; D007700:Kinetics; D008297:Male; D010755:Organophosphates / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity*; D013237:Stereoisomerism; D013552:Swine; D018675:Toxicity Tests / Q000379:methods
D002619:Chemical Warfare Agents; D010755:Organophosphates; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; C009374:tabun