Effects of enzyme inducers or inhibitors on the pharmacokinetics of intravenous parathion in rats

In order to find what form of hepatic cytochrome P450 (CYP) is involved in the metabolism of parathion to form paraoxon, rats were pretreated with the enzyme inhibitors, such as SKF 525-A and ketoconazole or enzyme inducers, such as dexamethasone, isoniazid, phenobarbital, and 3-methylcholanthrene. Parathion, 3 mg/kg, was infused in 1 min via the jugular vein. In rats pret reated with SKF 525-A or ketoconazole, nonspecific CYP inhibitors, the area under the plasma concentration-time curve from time zero to time infinity (AUC) and total body clearance (Cl) of parathion were significantly greater and slower, respectively, than those in respective control rats, suggestin g that parathion was metabolized by CYPs. In rats pretreated with dexametha sone (CYP3A23 inducer), the AUC was significantly smaller (41.5 compared wi th 52.5 mug min/mL), Cl was significantly faster (72.2 compared with 57.1 m L/min/kg), and the amounts and/or tissue-to-plasma ratios of parathion was significantly (or tended to be) smaller than those in control rats. However , the pharmacokinetic parameters of parathion were not significantly differ ent after pretreatment with other enzyme inducers compared with respective control rats. The above data suggested that parathion was metabolized to pa raoxon by dexamethasone-inducible CYP3A23, the induction of which was confi rmed by Western blot analysis. This was supported by in vitro intrinsic cle arance (Cl-int) of parathion to form paraoxon in hepatic microsomal fractio n; the Cl,, in rats pretreated with dexamethasone was significantly faster (0.0900 compared with 0.0290 mL/min/mg protein) than that in control rats. Copyright (C) 2000 John Wiley & Sons, Ltd.