Biodisposition of [3H]diisopropylfluorophosphate in mice

The disposition of [3H]diisopropylfluorophosphate (DFP) and its metabolites was studied in mice after iv treatment. In addition, disposition of [3H]DFP in selected tissues was correlated with cholinesterase activity and spontaneous activity following DFP treatment. Within 1 min of administration [3H]DFP had penetrated tissues and was already irreversibly bound. The tissue concentrations of [3H]DFP declined in a rapid fashion so that after 2 hr all concentrations were below 50 pg/mg tissue. The major portion of radioactivity was bound to tissue in the form of [3H]diisopropylphosphoric acid (DIP). There was a decline in [3H]DIP with time in all tissues except liver, kidneys, and fat, which reached a maximum at 30 min before declining. The only appreciable quantities of [3H]DIP remaining after 3 days were in liver and kidneys. There was also evidence that [3H]DFP was rapidly hydrolyzed to free [3H]DIP which was found in all tissues within 1 min of [3H]DFP administration. [3H]DIP concentrations were equivalent to or exceeded those of [3H]DFP in all tissues, except brain. Cholinesterase inhibition in plasma, diaphragm, and brain following DFP treatment (1 mg/kg, iv) was temporarily correlated with the concentrations of bound [3H]DIP in these same tissues between 1 hr and 3 days. Cholinesterase inhibition in brain and diaphragm did not correlate well with bound [3H]DIP at earlier time points which suggested the presence of noncholinesterase binding. DFP treatment (1 mg/kg) also induced motor hypoactivity which lasted up to 6 hr after iv injection. The time course of motor hypoactivity was not correlated with free [3H]DFP, bound [3H]DIP concentrations in the brain, or with cholinesterase inhibition in the brain, which suggested that noncholinesterase bound [3H]DIP was responsible for this CNS depression.