Effects of enzyme inducers and inhibitor on the pharmacokinetics of intravenous 2-(allylthio)pyrazine, a new chemoprotective agent, in rats.
In order to find what types of hepatic cytochrome P450 (CYP) isozymes are involved in the metabolism of 2-(allylthio)pyrazine (2-AP) in rats, enzyme inducers, such as phenobarbital, 3-methylcholanthrene, dexamethasone, or isoniazid, and an enzyme inhibitor, such as SKF 525-A were pretreated. After 1-min intravenous administration of 2-AP, 50 mg/kg, to rats pretreated with SKF 525-A (a non-specific CYP inhibitor in rats), the plasma concentrations were significantly higher, and the area under plasma concentration-time curve from time zero to time infinity (AUC) was significantly greater (1365 compared with 1034 microg min/mL) as a result of significantly slower total body clearance (Cl) (36.6 compared with 48.3 mL/min/kg) than those in control rats, indicating that 2-AP was metabolized by CYP isozymes. After 1-min intravenous administration of 2-AP, 50 mg/kg, to rats pretreated with dexamethasone (an inducer of CYP3A in rats), phenobarbital (an inducer of CYP2B1/2, 2C6, 2C7, and 3A1/2 in rats), and 3-methylcholanthrene (an inducer of CYP1A1/2 and 2A1 in rats), the plasma concentrations were significantly lower, and AUC was significantly smaller (27, 41 and 60% decrease, respectively, compared with respective control rats) owing to faster Cl [37 (p>0.05), 70 (p<0.001), and 150% (p<0.001) increase, respectively, compared with respective control rats].
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College of Pharmacy, Seoul National University, Shinlim-Dong, Kwanak-Gu, Seoul, Republic of Korea.
Kim
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Kim
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Lee
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D000588:Amines / Q000494:pharmacology; D000818:Animals; 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 / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D007538:Isoniazid / Q000494:pharmacology; D008297:Male; D010634:Phenobarbital / Q000494:pharmacology; D011335:Proadifen / Q000494:pharmacology; D011719:Pyrazines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
C104935:2-(allylthio)pyrazine; D000588:Amines; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D011719:Pyrazines; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; C025371:isoamylamine; D007538:Isoniazid; D010634:Phenobarbital