Effects of cytochrome P450 (CYP) inducers and inhibitors on ondansetron pharmacokinetics in rats: involvement of hepatic CYP2D subfamily and 3A1/2 in ondansetron metabolism.
The types of hepatic microsomal cytochrome P450 (CYP) isozymes responsible for the in-vivo metabolism of ondansetron in rats have not been reported. In this study, ondansetron at a dose of 8 mg kg(-1) was administered intravenously to rats pretreated with various inducers of CYP isozymes, such as 3-methylcholanthrene, orphenadrine citrate, isoniazid and dexamethasone phosphate (the main inducers of CYP1A1/2, 2B1/2, 2E1 and 3A1/2 in rats, respectively), and inhibitors, such as SKF-525A (a non-specific inhibitor of CYP isozymes), sulfaphenazole, quinine hydrochloride and troleandomycin (the main inhibitors of CYP2C6, 2D subfamily and 3A1/2 in rats, respectively). In rats pretreated with quinine hydrochloride and troleandomycin, the time-averaged non-renal clearance of ondansetron was significantly slower (48.9 and 13.2% decrease, respectively) than that in control rats. In rats pretreated with dexamethasone phosphate, the time-averaged non-renal clearance was significantly faster (18.2% increase) than that in control rats. The results suggest that ondansetron is primarily metabolized via the CYP2D subfamily and 3A1/2 in rats.
Yang
Si H
SH
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, San 56-1, Shinlim-Dong, Gwanak-Gu, Seoul 151-742, South Korea.
Lee
Myung G
MG
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000502:physiology*; D001798:Blood Proteins / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000502:physiology*; D051544:Cytochrome P-450 CYP3A; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008099:Liver / Q000201:enzymology*; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D017294:Ondansetron / Q000493:pharmacokinetics*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley
D001798:Blood Proteins; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D017294:Ondansetron; D001189:Aryl Hydrocarbon Hydroxylases; C465260:Cyp3a2 protein, rat; C465138:Cyp3a23-3a1 protein, rat; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A