Pharmacokinetic interaction between tamoxifen and ondansetron in rats: non-competitive (hepatic) and competitive (intestinal) inhibition of tamoxifen metabolism by ondansetron via CYP2D subfamily and 3A1/2.
OBJECTIVE
Tamoxifen and ondansetron were commonly metabolized via rat hepatic CYP2D subfamily and 3A1/2, and ondansetron is used to treat chemotherapy-induced nausea. The purpose of this study was to report the pharmacokinetic interaction between tamoxifen and ondansetron in rats.


METHODS
The pharmacokinetics of tamoxifen and ondansetron were evaluated after the intravenous and oral administration of tamoxifen, ondansetron, and both drugs together to rats. The Vmax (maximum velocity), Km (apparent Michaelis-Menten constant), CLint (intrinsic clearance), Ki (inhibition constant), and [I] (concentration of inhibitor in the liver and intestine)/Ki ratio of ondansetron were also measured.


RESULTS
The AUC0-infinitys of tamoxifen were significantly greater after both intravenous and oral administration with ondansetron compared to those of tamoxifen alone. The significantly slower hepatic and intestinal CLints for the disappearance of tamoxifen with both drugs together were due to inhibition of metabolism of tamoxifen by ondansetron via CYP2D subfamily and 3A1/2.


CONCLUSIONS
The significantly greater AUC0-infinity of tamoxifen after the intravenous administration of both drugs together could have possibly been attributable to a non-competitive (hepatic) inhibition of CYP2D subfamily- and 3A1/2-mediated tamoxifen metabolism by ondansetron. The significantly greater AUC0-infinity of tamoxifen after the oral administration of both drugs together could have been attributable to a competitive (intestinal) inhibition of CYP2D subfamily- and 3A1/2-mediated tamoxifen metabolism by ondansetron in addition to non-competitive inhibition in the liver.
Yang
Si Hyung
SH
College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu, Seoul, 151-742, South Korea.
Suh
Jung Hwa
JH
Lee
Myung Gull
MG
D000284:Administration, Oral; D000429:Alcohol Oxidoreductases / Q000378:metabolism*; D000818:Animals; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D004347:Drug Interactions; D007262:Infusions, Intravenous; D007413:Intestinal Mucosa / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D008861:Microsomes / Q000378:metabolism; D017294:Ondansetron / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013629:Tamoxifen / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*
D008565:Membrane Proteins; D013629:Tamoxifen; D017294:Ondansetron; D000429:Alcohol Oxidoreductases; D001189:Aryl Hydrocarbon Hydroxylases; C504568:Cyp2d1 protein, rat; C465260:Cyp3a2 protein, rat; C465138:Cyp3a23-3a1 protein, rat; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2