Effects of physostigmine on the pharmacokinetics of intravenous parathion in rats

It was reported that the area under the plasma concentration-time curve fro m time zero to time infinity (AUC) of parathion was significantly smaller, and the time-averaged total body clearance (Cl) of parathion was significan tly faster after intravenous administration of parathion to rats pretreated with dexamethasone than those in control rats. This was supported by signi ficantly faster intrinsic clearance of parathion to form paraoxon in hepati c microsomal fraction of rats pretreated with dexamethasone. The above data suggested that parathion was metabolized to paraoxon by dexamethasone-indu cible hepatic cytochrome P450 (CYP) 3A in rats. The purpose of this study i s to explain the protective effects of physostigmine against paraoxon toxic ity by suppressing CYP3A, and hence, decreasing formation of a toxic metabo lite, paraoxon. The pharmacokinetic changes of parathion and paraoxon were investigated after intravenous administration of parathion, 3 mg/kg, to con trol Sprague-Dawley rats, and the rats pretreated with physostigmine (100 m ug/kg, intraperitoneal injection 30 min before parathion administration). A fter a 1-min intravenous infusion of parathion to rats pretreated with phys ostigmine, the AUC of parathion (60.4 compared with 73.7 mug min/mL) was si gnificantly greater, Cl of parathion (49.7 compared with 40.7 mL/min/kg) wa s significantly slower, and amount of paraoxon recovered from liver, mesent ery and large intestine at 5 min was smaller than those in control rats. Ba sed on in vitro rat hepatic microsomal studies, physostigmine inhibited sig nificantly the erythromycin N-demethylase activity (1.03 compared with 0.92 4 nmol/mg protein/min), mainly mediated by hepatic cytochrome P450 3A in ra ts. The above data suggested that the formation of paraoxon was inhibited i n rats pretreated with physostigmine by inhibiting CYP3A. Copyright (C) 200 0 John Wiley & Sons, Ltd.