Tissue disposition of [3H]sarin and its metabolites in mice.

The biodisposition and metabolic fate of [3H]sarin was investigated in mice after iv administration of a sublethal dose (80 micrograms/kg). Within 1 min of administration, all tissues contained substantial quantities of radioactivity of which less than 10% represented [3H]sarin. The major portion of radioactivity corresponded to free [3H]isopropyl methylphosphonic acid (IMPA), the pharmacologically inactive hydrolytic product of [3H]sarin. Somewhat lesser quantities were present as bound [3H]IMPA which resulted from phosphorylation of protein. Plasma contained high concentrations of bound [3H]IMPA, consistent with sarin's very reactive nature, which were sustained throughout the time course. Plasma concentrations of free [3H]IMPA diminished rather quickly. The high concentrations of metabolites in kidneys implied that this organ played a major role in the detoxification and excretion of [3H]sarin. Large quantities of free and bound [3H]IMPA were also found in lung which suggested an important site for toxicity. Only trace quantities of [3H]sarin were found in brain after 15 min. The major portion of radioactivity was present as either free and bound [3H]IMPA or as nonextractable material which presumably was [3H]methylphosphonic acid. Examination of the time course of sarin-induced motor hypoactivity and hypothermia revealed an immediate onset of action that lasted for 24 hr. However, substantial quantities of bound [3H]IMPA remained in brain at 24 hr which suggested that only a small portion of phosphorylation in brain accounted for these pharmacological effects.