Pharmacokinetic Analysis of Increased Toxicity of 2-sec-Butylphenyl Methylcarbamate (BPMC) by Fenitrothion Pretreatment in Mice

Pharmacokinetk Analysis of Increased Toxicity of 2-sec-ButylphenylMethylcarbamate (BPMC) by Fenitrothion Pretreatment in Mice.TSUDA, S., MIYAOKA, T., IWASAKI, M., AND SHIRASU, Y. (1984).Fundam. Appl. Toxicol. 4, 724–730. The potentiating effectof O,O-dimethyl O-(3-methyl-4-nitrophenyl) phosphorothioate(fenitrothion) on the toxicity of 2-sec-butylphenyl methylcarbamate(BPMC) in male mice was analyzed pharmacokinetically. The animalspretreated by dietary administration of 1000 ppm fenitrothionfor 1 week (4.4% of the po LD50 daily) did not show toxic symptomsexcept for a slight decrease in body weight In the fenitrothion-pretreatedmice, toxicity of fenitrothion was not changed but a fivefoldpotentiation was observed in po and ip acute lethality and athreefold potentiation of iv lethality of BPMC. Toxic signsafter BPMC administration were similar regardless of fenitrothionpretreatment or of route of administration. Fenitrothion pretreatmentfollowed by BPMC administration (20 mg/kg po or 8 mg/kg iv,approximate LD5 in the pretreated mice) significantly increasedthe plasma BPMC concentration and the total area under the plasmaconcentration versus time curve (AUG_0-. The pretreatment increasedthe oral AUC_0-, more greatly than the iv AUC_0-, (for po, 6.3-fold;for iv, 2.0-fold). The oral systemic availability of BPMC (fractionreaching systemic circulation) was increased by fenitrothiontreatment to 3.3-fold. These results suggest that a major causeof the potentiation may be the increase in amount of BPMC inthe systemic circulation.