Purpose  

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 V _max (maximum velocity), K _m (apparent Michaelis–Menten constant), CL_int (intrinsic clearance), K _i (inhibition constant), and [I] (concentration of inhibitor in the liver and intestine)/K _i ratio of ondansetron were also measured.

Results  

The AUC_0–∞s 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 CL_ints 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 AUC_0–∞ 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 AUC_0–∞ 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.