Pharmacokinetic interaction between oltipraz and omeprazole in rats: Competitive inhibition of metabolism of oltipraz by omeprazole via CYP1A1 and 3A2, and of omeprazole by oltipraz via CYP1A1/2, 2D1/2, and 3A1/2.
In rats, oltipraz is metabolized via hepatic CYP1A1/2, 2B1/2, 2C11, 2D1/2, and 3A1/2, and omeprazole via hepatic CYP1A1/2, 2D1/2, and 3A1/2. Hence, pharmacokinetic interaction between oltipraz and omeprazole were evaluated after simultaneous single i.v. and p.o. administration of both drugs to rats. After i.v. administration of oltipraz (10 mg/kg) and omeprazole (20 mg/kg), the AUC of both drugs was significantly greater (32.3 and 28.1% increase for oltipraz and omeprazole, respectively) than those after each drug alone. This could have been due to a competitive inhibition of metabolism of oltipraz by omeprazole via CYP1A1 and 3A2, and of metabolism of omeprazole by oltipraz via CYP1A1/2, 2D1/2, and 3A1/2. This could be supported by the apparent inhibition constants (K(i)) and the concentrations of each drug in the liver. After oral administration of oltipraz (30 mg/kg) and omeprazole (40 mg/kg), the AUC of oltipraz was significantly greater (68.8% increase) than that after oltipraz alone. This could have been primarily due to an inhibition of intestinal metabolism of oltipraz by omeprazole. However, comparable AUC values of omeprazole between p.o. administration of omeprazole alone and both drugs could have been due to insufficient inhibitory effect of oltipraz on omeprazole metabolism in both the liver and intestine.
Lee
Dae Y
DY
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu, Seoul 151-742, South Korea.
Kim
Jin W
JW
Lee
Myung G
MG
D000284:Administration, Oral; D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001667:Binding, Competitive / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D003580:Cytochromes; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D009853:Omeprazole / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D011719:Pyrazines / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013871:Thiones; D013876:Thiophenes; D013997:Time Factors; D014018:Tissue Distribution
D065609:Cytochrome P-450 CYP1A2 Inhibitors; D003580:Cytochromes; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D011719:Pyrazines; D013871:Thiones; D013876:Thiophenes; C026209:oltipraz; D000429:Alcohol Oxidoreductases; D001189:Aryl Hydrocarbon Hydroxylases; C017170:Cyp1a2 protein, rat; C504568:Cyp2d1 protein, rat; C119985:Cyp2d2 protein, rat; C465260:Cyp3a2 protein, rat; C465138:Cyp3a23-3a1 protein, rat; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D009853:Omeprazole