Soman metabolites

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). 

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. 

Little PJ, Scimeca JA, Martin BR. 1988. Distribution of (3H)diisopropyl flourophosphate, (3H)soman, (3H)sarin, and their metabolites in mouse brain. Drug Metab Dispos 16(4) 515-520. 

Figure 9.17. Organophosphate inhibitors of acetylcholinesterase. a The catalytic mechanism, shown here for diiso-propylfluorophosphate(DFP).b Stmcturesof soman and tabun. Like DFP, these were developed during world war II as nerve gases , c Stractures of the insecticides parathion and malathion, and of paraoxon, which is the achve metabolite of parathion. (Malathion likewise requires conversion to malaoxon.) The arrow above the malathione stmcture indicates the esterase cleavage sites in its leaving group esterase cleavage occurs in human plasma and renders the molecule non-toxic.

Shih, M.L., McMonagle, J.D., Dolzine, T.W., Gresham, V.C. (1994). Metabolite pharmacokinetics of soman, sarin and GF in rats and biological monitoring of exposure to toxic OP agents. J. Appl Toxicol. 14 195-9. 

In addition, due to the reversibility of the binding reaction of sarin and soman to CarbE, it appears that CarbEs are involved in metabolic detoxification of these agents to their corresponding nontoxic metabolites isopropyl methylphosphonic acid (IMPA) and pinacolyl methylphosphonic acid (PMPA) (Jokanovic et al, 1996). 

FIGURE 52.1. Metabolic detoxification of warfare nerve agents tabun, sarin, soman, and VX in mammals in vivo. Chemical names of metabolites are EDMPA - ethyl dimethylaminophosphoric acid, IMPA - isopropyl methylphosphonic acid, PMPA - pinacolyl methyl-phosphonic acid, EMPA - ethyl methylphosphonic acid, and MPA - methylphosphonic acid. 

Barr, J.R., Driskell, W.J., Aston, L.S., Martinez, R.A. (2004). Quantitation of metabolites of the nerve agents sarin, soman, cyclohexylsarin, VX and Russian VX in human urine using isotope-dilution gas chromatography-mass spectrometry. J. Anal. Toxicol. 28 372-8. 

Toxicity of organophosphates can be potentiated 15-20-fold in rats and mice by pretreatment with a metabolite of tri-O-cresylphosphate, CBDP (2-0-cresyl)-4H-l,3,2-benzodioxa-phosphorin-2-oxide), which is an irreversible inhibitor of CarbEs. In similar studies, tetraisopropylpyrophosphoramide (iso-OMPA), or mipafox, an organophosphate-irreversible inhibitor of CarbEs, potentiates three-to fivefold the toxicity of several OPs (soman, DFP, and methylparathion) and carbamates (carbofuran, aldicarb, propoxur, and carbaryl). Inhibition of CarbEs by CBDP, iso-OMPA, or mipafox pretreatment, particularly in plasma, liver, heart, brain, and skeletal muscles, is a major contributory factor in the potentiation of toxicity of organophosphates and carbamates. Thus, the toxicity of any drug, pesticide, or other type of agent that is normally detoxified by CarbEs, could be potentiated by pre-exposure to an organophosphorus or other carboxylesterase inhibitor. 

The elimination of VX deviates from that of soman. As observed in the toxicokinetic smdies, the elimination of VX proceeds much slower than that for the G-agents. In addition to the major detoxification route of VX, which leads to the formation of 0-ethyI methylphosphonic acid, it cannot be excluded that toxic metabolites will be formed. Possible toxic metabolites are the deal-kylated form of VX or desethyl-VX and the N-oxide of VX. Neither metabolite has been found in blood samples taken for toxicokinetic experiments. In vitro experiments, in which high concentrations of VX (10 p,g/mL) were incubated in plasma or fiver homogenate, did not yield any of these toxic metabolites either. However, desethyl-VX could be detected in reasonable amounts when plasma was derived from blood that was drawn in mbes with EDTA as anticoagulant. EDTA binds metal ions that are essential for the enzymatic hydrolysis of VX, which leads to the formation of EMPA. When that route is inhibited, the formation of desethyl-VX may increase. ... 

Little, P.J., Scimeca, J.A., and Martin, B.R., Distribution of [ H]diisopropylfluorophos-phate, [ H] soman, [ H] sarin and their metabolites in mouse brain. Drug Metab. Dispos., 16,515, 1988. 

Harris, L.W., Braswell, L.M., Fleisher, J.H., and Cliff, W.J., Metabolites of pinacolyl methylphosphonofluoridate (soman) after enzymatic hydrolysis in vitro, Biochem. Pharmacol., 13, 1129, 1964. 

Lenz, D.E., Boisseau, J., Maxwell, D.M., and Heir, E., Pharmacokinetics of soman and its metabolites in rats, Proceedings of the 6th Medical Chemical Defense Bioscience Review, Aberdeen Proving Ground, MD, U.201, AD B121516, 1987. 

Soman, A.G. Gloer, J.B. "New Bioactive Metabolites from the Mycoparasitic Fungi Mortierella vinaceae and Neocosmospora vasinfecta", Abstracts of Papers, 38th Annual Meeting of the American Society of Pharmacognosy, American Society of Pharmacognosy Iowa City, Iowa, 1997. 

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