The in vivo time course of
cholinesterase inhibition was measured in brain, lung, spleen, hind limb skeletal muscle, diaphragm, intestine, kidney, heart, liver, and plasma of rats receiving 90 micrograms/kg
soman, im. This dose of
soman produced severe
respiratory depression and transient
hypertension, but no significant changes in the cardiac output or heart rate of anesthetized rats. The rate and maximal extent of in vivo
cholinesterase inhibition by
soman varied widely among the tissues. Although cardiac output was unchanged by
soman administration, the blood flow in heart, brain, and lung (bronchial arterial flow and arteriovenous shunts) was increased, whereas blood flow in spleen, kidney, and skeletal muscle was decreased. The relative importance of tissue blood flow, tissue levels of
cholinesterase and
acetylcholinesterase, and tissue levels of
soman-detoxifying
enzymes (
diisopropyl-fluorophosphatase and
carboxylesterase) in determining the in vivo rate and maximal extent of
cholinesterase inhibition was examined by multiple regression analysis. The best multiple regression model for the maximal extent of
cholinesterase inhibition could explain only 63% of the observed variation. The best multiple regression model for the in vivo rate of
cholinesterase inhibition contained three independent variables (blood flow,
carboxylesterase, and
cholinesterase) and could account for 94% of the observed variation. Of these three variables blood flow was the most important, accounting for 79% of the variation in the in vivo rate of
cholinesterase inhibition. This suggests that it may be possible to use a flow-limited physiological pharmacokinetic model to describe the kinetics of in vivo
cholinesterase inhibition by
soman.