Cyclosarin metabolites

Evans, R.A., Jakubowski, E.M., Muse, W.T., Matson, K., Hulet, S.W., Mioduszewski, R.J., Thomson, S.A., Totura, A.L., Retmer, J.A., Crouse, C.L. (2008). Quantification of sarin and cyclosarin metabolites isopropyl methylphosphonic acid and cyclohexyl methylphosphonic acid in minipig plasma using isotope-dilution and liquid chromatography-time-of-flight mass spectrometry. J. Anal. Toxicol. 32(1) 78-85. 

Sarin and its corresponding nontoxic hydrolysis products (IMPA, and additional methyl phosphonic acids) are predominantly eliminated via the kidneys which are thus more important for detoxification than the liver (Little et al, 1986 Waser and Streichenberg, 1988). Urinary excretion happens quite rapidly as demonstrated for single dose s.c. application of sarin, cyclosarin, and soman to rats (Shih et al, 1994). The terminal elimination half-life was found to be 3.7 =E 0.1 h for sarin and 9.9 0.8 h for cyclosarin. In contrast soman showed a biphasic elimination with terminal half-fives of about 18.5 h and 3.6 h (Shih et al, 1994). Maximum peak levels of sarin metabolites in urine were detected 10-18 h after exposure (Minami et al, 1997) and after 2 days hydrolyzed sarin metabolites had been excreted nearly quantitatively (Shih et al, 1994). In contrast, even at 5 days post-exposure soman metabolite recovery was only 62% (Shih et al, 1994). Excretion of soman from blood, fiver, and kidney compartments following cfiemical and enzymatic hydrolysis is considered a first-order elimination process (Sweeney et al, 2006). 

Barr JR, Driskell WJ, Aston LS, Martinez RA. Quantitation of metabolites of the nerve agents sarin, soman, cyclosarin, VX and Russian VX in human urine using isotope-dilution gas chromatography-tandem mass spectrometry. J Anal Toxicol, 2004 28 371-378. 

Shih et al. (1994) injected rats subcutaneously with a single dose of 75]Hg/kg of sarin, cyclosarin, and soman, and measured excretion of the hydrolyzed metabolites and the alkylmethylphosphonic acids, including IMPA and corresponding MPAs. MPA was a major and common metabolite of the three compounds. Urinary excretion over the first 24 h accounted for approximately 90% of the administered doses of sarin and cyclosarin. Almost total recoveries of the given doses for sarin and cyclosarin in metabolite form were obtained from the urine. Urinary elimination was found to be rapid and the terminal elimination half-life of sarin metabolites in urine was 3.7h. Most of the administered dose of sarin was retrieved from the urine in a metabolite form after 2 days. The terminal elimination half-life of cyclosarin in urine was 9.9 h. Soman metabolite showed a biphasic elimination curve with terminal half-lives of 18.5 and 3.6 h. Soman was excreted at a slower rate, with a recovery of only 62%. The first phase of elimination of soman results from enzymatic hydrolysis of the inactive P( + ) isomers, and the slower phase is from the active P( - ) isomers (Benschop and De Jong, 1991). The elimination study in rats determined IMPA in blood up to 14 h after exposure, CHMPA up to 2 days, and PMPA up to at least 3 days. 

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