French_1985_Pestic.Biochem.Physiol_24_53

R(+)-Ethyl S-propyl methylphosphonothioate is bioactivated both in vivo and when perfused through isolated liver to give a product which is much more active as an inhibitor of acetylcholinesterase than the parent compound. The bioactivation does not occur in hepatectomised animals. Acetylcholinesterase inhibited by the active metabolite is not reactivated by pyridine-2-aldoxime methanesulphonate (P2S), whereas enzyme inhibited by the parent compound and its S(-) enantiomer is reactivatable. Attempts to identify the active metabolite were unsuccessful and experiments to explore its stability were inconclusive. Extensive in vitro studies of the inhibition of acetylcholinesterase by the enantiomers of ethyl S-propyl methylphosphonothioate and ethyl S-diisopropylaminoethyl methylphosphonothioates and subsequent reactivation of the enzyme by P2S showed that (a) there are large differences between the rates of inhibition of the R and S enantiomers of both compounds, (b) reactivation profiles are critically dependent on reaction conditions, and (c) the reactivation profiles of the R and S enantiomers of the former compound are indistinguishable under all conditions whereas differences are observed under some conditions for the latter pair of enantiomers. The results are discussed in terms of the possibility that the S-oxide of R(+)-ethyl S-propyl methylphosphonothioate is the active metabolite and it is concluded that this is unlikely.