Metabolism of O,O,S-trimethyl phosphorothioate in rats after oral administration of a toxic dose,and the effect of coadministration of its antagonistic thionate isomer

The in vivo metabolism of ¹⁴CH₃S]- and ¹⁴CH₃O]O,O,S-trimethyl phosphorothioate (OOS) was followed in rats after oral administration of threshold or LD₅₀ toxic doses of 20 or 60 mg/kg. Similar metabolic studies were conducted with coadministration of 1% O,O,O-trimethyl phosphorothionate (OOO), which prevented all signs of delayed toxicity, including weight loss. When administered alone, OOS was metabolized mainly (50–60%) via removal of the CH₃S moiety, which was largely converted to expired CO₂. Approximately 20% of the compound was O-demethylated, presumably by conjugation with glutathione, and then further metabolized to CO₂. Major urinary products were identified as O,O-dimethyl phosphoric acid (50–60%) and O,S-dimethyl phosphorothioic acid (～20%). Coadministration of OOO caused a slight decrease (～5%) in the cleavage of the CH₃S moiety, indicated by a reduction in ¹⁴CO₂ from ¹⁴CH₃S]OOS and a quantitatively similar increase in the formation of O,S-dimethyl phosphoric acid. Limited pharmacokinetic studies indicated that OOS was rapidly absorbed and distributed throughout the body. Coadministration of 1% OOO caused a slight increase in the blood half-life of parent OOS when administered at 60 mg/kg. It was concluded that a small proportion of the cleavage of the CH₃S moiety from OOS is involved in the intoxication process, and that this intoxication reaction is specifically inhibited by OOO.