The effects of blood flow and detoxification on in vivo cholinesterase inhibition by soman in rats.
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.
D000110:Acetylcholinesterase / Q000032:analysis; D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D002302:Cardiac Output / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D002802:Cholinesterases / Q000032:analysis; D003326:Coronary Circulation / Q000187:drug effects; D004950:Esterases; D006867:Hydrolases / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced; D007668:Kidney / Q000098:blood supply; D008297:Male; D009132:Muscles / Q000098:blood supply; D044345:Phosphoric Triester Hydrolases; D011652:Pulmonary Circulation / Q000187:drug effects; D051381:Rats; D012039:Regional Blood Flow / Q000187:drug effects*; D012119:Respiration / Q000187:drug effects; D012999:Soman / Q000633:toxicity*; D013154:Spleen / Q000098:blood supply; D014018:Tissue Distribution
D002800:Cholinesterase Inhibitors; D012999:Soman; D006867:Hydrolases; D004950:Esterases; D002265:Carboxylic Ester Hydrolases; D000110:Acetylcholinesterase; D002802:Cholinesterases; D044345:Phosphoric Triester Hydrolases; C020061:diisopropyl-fluorophosphatase