Relationship between the biodisposition of [3H]soman and its pharmacological effects in mice

The iv administration of soman (25 micrograms/kg) resulted in inhibition of cholinesterase activity in plasma, brain, and diaphragm, as well as depression of spontaneous activity and rectal temperature in mice. The motor activity and rectal temperature of these animals had returned to control levels within 24 hr, but cholinesterase activity was not fully recovered after 3 days. Following iv administration of [3H]soman (25 micrograms/kg), only trace quantities of [3H]soman were found in all tissues as early as 1 min after injection. Almost half of the injected material was present in the form of free [3H]pinacolylmethylphosphoric acid (PMPA) within 1 min of injection of [3H]soman. The concentrations of [3H]PMPA fell by more than 50% by 1 hr. High concentrations of covalently bound [3H]PMPA were present in all tissues immediately after [3H]soman treatment, particularly in lungs, heart, and kidneys. These concentrations declined slowly and after 8 hr, the quantities of bound [3H]PMPA in most tissues had fallen by less than 50%. The radioactivity in brain was identified as bound and free [3H]PMPA, nonextractable radioactivity (presumably [3H]methylphosphonic acid), and only traces of [3H]soman. It appears that phosphorylation of cholinesterase in the central nervous system is not solely responsible for depression of motor activity and rectal temperature.