Development of a physiologically based model for the toxicokinetics of C(+/-)P(+/-)-soman in the atropinized guinea pig.
A physiologically based model was developed which describes the in vivo toxicokinetics of the highly reactive nerve agent C(+/-)P(+/-)-soman at doses corresponding to 0.8-6 LD50 in the atropinized guinea pig. The model differentiates between the summated highly toxic C(+/-)P(-)-soman stereoisomers at supralethal doses and the individual nontoxic C(+/-)P(+)-isomers. Several toxicant-specific parameters for the soman stereoisomers were measured in guinea pig tissue homogenates. Cardiac output and blood flow distribution were measured in the atropinized, anesthetized, and artificially ventilated guinea pig. The model was validated by comparison of the time courses for the blood concentrations of the two pairs of stereoisomers in the guinea pig after i.v. bolus administration with the blood concentrations predicted by the model. The predictions put forward for the summated C(+/-)P(-)-isomers are in reasonable agreement with the experimental data obtained after doses corresponding to 2 and 6 LD50. In view of large differences in the rates of hydrolysis of the C(+/-)P(+)-isomers, these two isomers had to be differentiated for satisfactory modeling of both isomers. In order to model the toxicokinetics of C(+/-)P(-)-soman at a dose of 0.8 LD50, the almost instantaneous elimination of the C(+)P(-)-isomer at that dose had to be taken into account. The sensitivity of the predictions of the model to variations in the parameters has been studied with incremental sensitivity analysis. The results of this analysis indicate that extension to a model involving four individual stereoisomers is desirable in view of large differences in the biochemical characteristics of the two C(+/-)P(-)- and C(+/-)P(+)-isomers.
Langenberg
J P
JP
TNO Prins Maurits Laboratory, Rijswijk, The Netherlands.
van Dijk
C
C
Sweeney
R E
RE
Maxwell
D M
DM
De Jong
L P
LP
Benschop
H P
HP
D000110:Acetylcholinesterase / Q000097:blood / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000201:enzymology; D002302:Cardiac Output / Q000187:drug effects; D006168:Guinea Pigs; D007668:Kidney / Q000201:enzymology; D008099:Liver / Q000201:enzymology; D008168:Lung / Q000201:enzymology; D008297:Male; D008954:Models, Biological; D009132:Muscles / Q000201:enzymology; D011485:Protein Binding; D012039:Regional Blood Flow / Q000187:drug effects; D012680:Sensitivity and Specificity; D012999:Soman / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D013237:Stereoisomerism
D012999:Soman; D000110:Acetylcholinesterase