Alteration of the Efficacy and Toxicity of Clinically Useful Drug Esters by Organophosphate Inhibitors

摘要

The effects of soman pretreatment of the pharmacokinetics of three drug esters were studied in guinea pigs. Soman was administered subcutaneously either 1 hr or 12 hr prior to intravenous administration of the drug ester. The dose of soman (22.5 ug/kg) was approximately 90 percent of the LD50 in the guinea pig (25 ug/kg). The animals were anesthetized with pentobarbital and blood samples (0.5 ml) were withdrawn at several time periods over a 3-hr interval. Plasma from these blood samples was analyzed for acetylcholinesterase activity and for the parent compound and its metabolites. Acetylcholinesterase activity was not measurable at the 1-hr time period and was approximately 30 percent of the control value at the 12-hr period. Soman pretreatment did not significantly change the half-life of either meperidine or chloramphenicol succinate. The half-life of lidocaine was reduced by 4-fold with the 12-hr pretreatment but was not significantly different from control with the 1-hr pretreatment. These results suggest that soman pretreatment has very little effect on hepatic drug metabolism at the dose which is near-lethal in the guinea pig. Larger doses in species less sensitive to soman may produce changes in drug metabolism.