PHARMACOKINETIC STUDY OF P-CHLORONITROBENZENE IN HUMANS SUFFERING FROM ACUTE-POISONING

The pharmacokinetics of p-chloronitrobenzene (p-CNB) in human subjects suffering from acute poisoning was studied from the urinary excretion of p-CNB metabolites. The time courses for excretion of five metaboli tes-2-chloro-5-nitrophenol, N-acetyl-S-(4-nitrophenyl)-L-cysteine, 2,4 -dichloroaniline, p-chloroaniline, and 2-amino-5-chlorophenol-were det ermined by reversed-phase HPLC analysis of urine collected from six su bjects during their hospitalization after accidental exposure to p-CNB . The cumulative excretion amount at infinite time (X) and mean reside nce time for each metabolite were estimated by moment analysis of excr etion rate vs. the time curve. The rate constants for p-CNB metabolism were calculated by nonlinear least squares fitting of the time course data using a one-compartment model. The results indicated that the av erage values of the ratio of excreted amount of each metabolite to the total amount of the five metabolites (X(infinity) metabolite/X(infini ty)Total) and mean residence time in the six subjects were, respective ly: 12.2% and 6.7 days for 2-chloro-5-nitrophenol, 48.0% and 7.0 days for N-acetyl-S-(4-nitrophenyl)-L-cysteine, 1.2% and 3.7 days for 2,4-d ichloroaniline, 29.9% and 10.0 days for p-chloroaniline, and 8.7% and 6.0 days for 2-amino-5-chlorophenol. The average values of rate consta nts in the metabolism of p-CNB to 2-chloro-5-nitrophenol, N-acetyl-5-( 4-nitrophenyl)-L-cysteine, and p-chloroaniline were 0.021, 0.082, and 0.067 day-1, respectively. Similarly those in further metabolism of p- chloroaniline for C-chlorination, C-hydroxylation, and N-conjugation w ere 0.205, 1.206, and 3.526 day-1, respectively. It was considered tha t the rates of transformation of p-CNB to 2-chloro-5-nitrophenol and p -chloroaniline were slow, but the resulting p-chloroaniline was metabo lized relatively rapidly in the human body.