The disposition of [3H]diisopropylfluorophosphate in guinea pigs after inhalation

The disposition of the organophosphate anticholinesterase, diisopropylfluorophosphate (DFP), was studied in guinea pigs after inhalation exposure. The tissue disposition of [3H]DFP and its metabolites was determined in the major tissues of the guinea pig from 5 min to 24 hr after treatment. [3H]DFP rapidly penetrated all tissues, where it was quickly hydrolyzed to the inactive metabolite, free [3H]diisopropylphosphoric acid ([3H]DIP), or was covalently bound to tissue in the form of bound [3H]DIP. Tissue concentrations of [3H]DFP and free [3H]DIP followed a biphasic curve, with an initial phase representing a very rapid decrease in tissue concentrations, followed by a slower phase of tissue clearance. Concentrations of free [3H]DIP generally exceeded those of [3H]DFP; however, by 4 hr the greater portion of the radioactivity in all the tissues was in the form of bound [3H]DIP. Bound [3H]DIP levels did not follow a biphasic clearance curve and declined at a slower rate than [3H]DFP and free [3H]DIP tissue levels. By 5 min the greatest accumulation of bound [3H]DIP occurred in the liver (nearly 20% of the total body burden), with a noticeably small amount in the brain (0.1%). Tissue concentrations of nonextractable radioactivity, thought to be [3H]monoisopropylphosphoric acid ([3H]MIP), were appreciable and persistent throughout the time course. Total cholinesterase activity in the brain and red blood cells was inhibited by about 90%, with plasma pseudo- and true cholinesterase activity inhibited by 99 and 97%, respectively. The time course of recovery of enzyme activity in these tissues failed to correlate with the respective tissue levels of either bound [3H]DIP or [3H]MIP.(ABSTRACT TRUNCATED AT 250 WORDS)