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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

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Abstract

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), CLint (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 AUC0–∞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 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–∞ 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–∞ 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.

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Abbreviations

Ae 0–24h :

Percentage of the dose excreted in the 24-h urine

AUC0–∞ :

Total area under the plasma concentration–time curve from time zero to time infinity

C max :

Peak plasma concentration

CL:

Time-averaged total body clearance

CLR :

Time-averaged renal clearance

CLNR :

Time-averaged non-renal clearance

CLint :

Intrinsic clearance

CYP:

Cytochrome P450

F :

Extent of absolute oral bioavailability

FMO:

Flavin-containing monooxygenase

GI24h :

Percentage of the dose recovered from the gastrointestinal tract (including its contents and feces) at 24 h

HPLC:

High-performance liquid chromatography

I:

Inhibitor

K i :

Inhibition constant

K m :

Apparent Michaelis–Menten constant

T max :

Time to reach C max

V max :

Maximum velocity

V ss :

Apparent volume of distribution at steady state

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Acknowledgment

This study was supported in part by 2008 BK21 Project for Applied Pharmaceutical Life Sciences.

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Authors and Affiliations

  1. College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu, Seoul, 151-742, South Korea

    Si Hyung Yang, Jung Hwa Suh & Myung Gull Lee

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  1. Si Hyung Yang
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  2. Jung Hwa Suh
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Correspondence to Myung Gull Lee.

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Yang, S.H., Suh, J.H. & Lee, M.G. 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. Cancer Chemother Pharmacol 65, 407–418 (2010). https://doi.org/10.1007/s00280-009-1043-4

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