Relationship between the pharmacological effects and the biodisposition of [3H]diisopropylfluorophosphate in mice after inhalation.

The biodisposition of [3H]diisopropylfluorophosphate (DFP) and its metabolites was studied in mice after inhalation administration. In addition, the time course of DFP-induced cholinesterase inhibition in selected tissues, hypothermia, and motor coordination were studied to determine a possible correlation with [3H]DFP, or its metabolites. The time course of tissue concentrations of [3H]DFP showed that [3H]DFP rapidly penetrated all tissues and was quickly hydrolyzed to [3H]diisopropylphosphoric acid (free [3H]DIP) or was covalently bound to tissue (bound [3H]DIP). By 1 hr, the greater portion of the radioactivity was in the form of bound [3H]DIP. Cholinesterase inhibition in brain, lung, diaphragm, and plasma was temporally related to concentrations of bound [3H]DIP between 5 min and 1 day, except at early time points for the lung. Motor incoordination (rotarod test) produced by DFP exposure had a rapid onset, with complete recovery by 10 hr. DFP-induced hypothermia (rectal temperature) had a very similar time-course profile to that of motor incoordination. The time course of hypothermia and motor incoordination was correlated with neither free [3H]DFP nor bound [3H]DIP concentrations in the brain, nor with cholinesterase inhibition in brain. These findings suggest that non-cholinesterase bound [3H]DIP may contribute to the depression of these centrally mediated effects.