Pharmacokinetic analysis of increased toxicity of 2-sec-butylphenyl methylcarbamate (BPMC) by fenitrothion pretreatment in mice.

The potentiating effect of 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 animals pretreated by dietary administration of 1000 ppm fenitrothion for 1 week (4.4% of the po LD50 daily) did not show toxic symptoms except for a slight decrease in body weight. In the fenitrothion-pretreated mice, toxicity of fenitrothion was not changed but a fivefold potentiation was observed in po and ip acute lethality and a threefold potentiation of iv lethality of BPMC. Toxic signs after BPMC administration were similar regardless of fenitrothion pretreatment or of route of administration. Fenitrothion pretreatment followed by BPMC administration (20 mg/kg po or 8 mg/kg iv, approximate LD5 in the pretreated mice) significantly increased the plasma BPMC concentration and the total area under the plasma concentration versus time curve (AUC0-infinity). The pretreatment increased the oral AUC0-infinity more greatly than the iv AUC0-infinity (for po, 6.3-fold; for iv, 2.0-fold). The oral systemic availability of BPMC (fraction reaching systemic circulation) was increased by fenitrothion treatment to 3.3-fold. These results suggest that a major cause of the potentiation may be the increase in amount of BPMC in the systemic circulation.