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

Abstract

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 pretreated 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, suggesting that parathion was metabolized by CYPs. In rats pretreated with dexamethasone (CYP3A23 inducer), the AUC was significantly smaller (41.5 compared with 52.5 microg min/mL), Cl was significantly faster (72.2 compared with 57.1 mL/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 different after pretreatment with other enzyme inducers compared with respective control rats. The above data suggested that parathion was metabolized to paraoxon by dexamethasone-inducible CYP3A23, the induction of which was confirmed by Western blot analysis. This was supported by in vitro intrinsic clearance (Cl(int)) of parathion to form paraoxon in hepatic microsomal fraction; the Cl(int) in rats pretreated with dexamethasone was significantly faster (0.0900 compared with 0.0290 mL/min/mg protein) than that in control rats.

Pharmacokinetics of Baicalin in Rats and its Interactions with Cyclosporin A, Quinidine and SKF-525A: A Microdialysis Study

“…This suggests that baicalin might be metabolized in rats by cytochrome P450 catalysis, which in our study was subsequently verified by treatment with a non-specific CYPs inhibitor, SKF-525A. Pretreatment with SKF-525A has been reported to cause higher plasma concentration, greater plasma AUC and slower total body Cl for some drugs [13], indicating that the drugs were metabolized by CYP isozymes. However, our results were distinct from the above-mentioned results in that plasma baicalin AUC was lower, while the total body Cl was faster in the SKF-525A treated rats.…”

Vitamin K3 (menadione) redox cycling inhibits cytochrome P450-mediated metabolism and inhibits parathion intoxication

“…Previous studies have shown that one h pretreatment of rats with the CYP inhibitor, SKF525A, significantly increased plasma levels of parathion, providing experimental evidence that CYP inhibition can alter its pharmacokinetics (Hurh et al, 2000). We found that treatment of rats with menadione 20 min after parathion caused significant increases in serum and brain parathion levels.…”

Hepatobiliary Excretion of Berberine

“…Until now, almost no study has reported which P450 isoform is more likely to be involved in berberine metabolism, and SKF-525A was chosen to inhibit berberine metabolism without P450 form selectivity, because it can block metabolic activities of all P450 forms tested to various degrees, depending on the P450 form (Ono et al, 1996). Pretreatment with SKF-525A has been reported to cause higher plasma concentration, greater plasma AUC and slower total body CL for some drugs (Bu et al, 2000;Hurh et al, 2000), indicating the drugs were metabolized by P450 isozymes. In this study, the berberine concentration and AUC in plasma were not statistically different from those in the control rats, which could be due to rapid redistribution of berberine into bile, since the resultant AUC and CL of bile were significantly greater and slower, respectively.…”