Effect of enzyme inducers and inhibitors on the pharmacokinetics of oltipraz in rats.
A series of in-vitro and in-vivo experiments, using various inducers and inhibitors of hepatic microsomal cytochrome P450 (CYP) isozymes, was conducted to study oltipraz pharmacokinetics in rats. In in-vivo studies, oltipraz at a dose of 10 mg kg(-) was administered intravenously to rats. In rats pretreated with SKF 525-A (a nonspecific CYP isozyme inhibitor in rats; n-9), the time-averaged total body clearance (CL) of oltipraz was significantly slower (56.6% decrease) than that in untreated rats (n=9). This indicated that oltipraz is metabolized via CYP isozymes in rats. Hence, various enzyme inducers or inhibitors were used in in-vitro and in-vivo studies in rats. In rats pretreated with 3-methylcholanthrene (n=9 and 8 for untreated and treated groups, respectively), phenobarbital (n=7 and 10 for untreated and treated groups, respectively) or dexamethasone (n=7 and 12 for untreated and treated groups, respectively) (main inducers of CYP1A1/2, 2B1/2 and 3A1/2 in rats, respectively), the CL values were significantly faster (38.4, 94.4 and 33.6% increase, respectively). In rats pretreated with sulfaphenazole (n=8 and 9 for untreated and treated groups, respectively), quinine (n=7 and 9 for untreated and treated groups, respectively) or troleandomycin (n=8 and 9 for untreated and treated groups, respectively) (main inhibitors of CYP2C11, 2D1 and 3A1/2 in rats, respectively), the CL values were significantly slower (31.0, 27.6 and 36.3% decrease, respectively). The in-vivo results with various enzyme inhibitors correlated well with the in-vitro intrinsic clearance for disappearance of oltipraz (CL(int)) (n=5, each). The above data suggested that oltipraz could be metabolized in male rats mainly via CYP1A1/2, 2B1/2, 2C11, 3A1/2 and 2D1.
Bae
Soo Kyung
SK
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu, Seoul 151-742, Korea.
Lee
Shin Jung
SJ
Kim
Young Hoon
YH
Kim
Taekrho
T
Lee
Myung Gull
MG
D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007538:Isoniazid; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008748:Methylcholanthrene; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D023421:Models, Animal; D010634:Phenobarbital; D011719:Pyrazines / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013871:Thiones; D013876:Thiophenes
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D011719:Pyrazines; D013871:Thiones; D013876:Thiophenes; D008748:Methylcholanthrene; C026209:oltipraz; D003577:Cytochrome P-450 Enzyme System; D007538:Isoniazid; D010634:Phenobarbital