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 |
| |
Authors: | A.J. Gray T.R. Fukuto |
| |
Affiliation: | Division of Toxicology and Physiology, Department of Entomology, University of California, Riverside, California 92521 USA |
| |
Abstract: | 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. |
| |
Keywords: | To whom correspondence should be addressed at Central Toxicology Laboratory Imperial Chemical Industries PLC Alderley Park Nr. Macclesfield Cheshire SK10 4TJ England. |
本文献已被 ScienceDirect 等数据库收录! |
|