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 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.
Hurh
E
E
College of Pharmacy, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu, Seoul, Republic of Korea.
Lee
E
E
Lee
A
A
Kim
Y
Y
Kim
S
S
Kim
S
S
Lee
M
M
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D015153:Blotting, Western; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007306:Insecticides / Q000493:pharmacokinetics*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D007538:Isoniazid / Q000494:pharmacology; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D010261:Paraoxon / Q000493:pharmacokinetics; D010278:Parathion / Q000097:blood / Q000493:pharmacokinetics*; D010634:Phenobarbital / Q000494:pharmacology; D011335:Proadifen / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007306:Insecticides; D007527:Isoenzymes; D008748:Methylcholanthrene; D010278:Parathion; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; D001189:Aryl Hydrocarbon Hydroxylases; C465138:Cyp3a23-3a1 protein, rat; D051544:Cytochrome P-450 CYP3A; D010261:Paraoxon; D007654:Ketoconazole; D007538:Isoniazid; D010634:Phenobarbital