Factors affecting the hepatic biotransformation of the phosphorothioate pesticide chlorpyrifos

Following single-pass perfusion of mouse livers in situ with the organophosphate pesticide chlorpyrifos, the cholinesterase inhibitor chlorpyrifos oxon could not be detected in effluent perfusate. Steady-state, with respect to chlorpyrifos, was achieved in 36-48 min, at which time the extraction ratio was 0.46. The hepatic disposition of chlorpyrifos was not affected changes in perfusate flow rates (provided the flow rates maintained viable livers), but was altered by changes in the free fraction of chlorpyrifos within perfusate. However, under no conditions did chlorpyrifos oxon appear in effluent perfusate. Pretreatment of mice with phenobarbital enhanced the production of chlorpyrifos oxon from chlorpyrifos by mouse hepatic microsomes in vitro, but antagonized the acute toxicity of chlorpyrifos. Phenobarbital pretreatment increased the steady-state extraction ratio of chlorpyrifos to 0.94, but did not lead to the presence of chlorpyrifos oxon in effluent perfusate. Thus the enhanced hepatic detoxification of chlorpyrifos following phenobarbital pretreatment probably accounts for the antagonism of the acute toxicity afforded by phenobarbital pretreatment.