A physiologically based model for the toxicokinetics of C(±)P(±)-soman in the atropinized guinea pig and marmoset - Effect of scavengers and hydrolytic enzymes promoting elimination
conference paper
Previously, we developed a physiologically based model describing the toxicokinetics of the summed C(±)P(-)-isomers and of the individual C(±)P(+)-isomers in anesthetized, atropinized and mechanically ventilated guinea pigs after intoxication with i.v. doses of 0.8 – 6 LD50 of C(±)P(±)-soman. Some improved parameters have been introduced into this model, which leads to a better prediction of the C(±)P(-)-soman concentrations in blood. Furthermore, the model was extended to the toxicokinetics in anesthetized, atropinized and mechanically ventilated marmosets after intoxication with i.v. doses of 2 – 6 LD50 of C(±)P(±)-soman. The model was used to predict the efficacy of i.v.-administered prophylactic agents that promote elimination processes of C(±)P(±)-soman. On a molar basis, sufficient protection against intoxication with 2 – 5 LD50 of C(±)P(±)-soman is offered by an i.v. dose of human butyrylcholinesterase corresponding with 0.5 - 0.7 times the C(±)P(±)-soman dose in both species. These predictions correspond with results obtained in protection experiments performed in mice, rats and rhesus monkeys (Ashani et al., 1993). Furthermore, modeling predicts that enzymes capable of hydrolyzing C(±)P(-)- soman should be approximately as effective as the endogenous enzymes for hydrolysis of C(-)P(+)-soman in order to achieve sufficient protection against an i.v. dose of 2 LD50 of C(±)P(±)-soman.
TNO Identifier
526826
Source title
BioScience 2000, US Army Medical Defense Bioscience Review, 4-9 June 2000
Pages
98-107
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