Can celecoxib affect P-glycoprotein-mediated drug efflux? A microPET study

de Vries, Erik F.J.; Doorduin, Janine; Vellinga, Namkje A.R.; van Waarde, Aren; Dierckx, Rudi A.; Klein, Hans C.

doi:10.1016/j.nucmedbio.2008.01.005

« Previous Next »Nuclear Medicine and Biology
Volume 35, Issue 4 , Pages 459-466, May 2008

Can celecoxib affect P-glycoprotein-mediated drug efflux? A microPET study

Erik F.J. de Vries
- Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands
- Corresponding author. Tel.: +31 50 3613311; fax: +31 50 3611687.
Janine Doorduin
- Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands
Namkje A.R. Vellinga
- Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands
Aren van Waarde
- Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands
Rudi A. Dierckx
- Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands
Hans C. Klein
- Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands
- Department of Psychiatry, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands

Received 11 December 2007; accepted 11 January 2008. published online 04 April 2008.

Abstract

Introduction

P-glycoprotein (Pgp) is an efflux pump that protects vital organs like the brain from toxic substances, but which is also associated with therapy resistance. The anti-inflammatory drug celecoxib potentiates the efficacy of several cytostatic and neurotropic drugs that are known Pgp substrates. To clarify whether Pgp is involved in the sensitizing effect of celecoxib, we investigated in vivo whether celecoxib is a substrate of Pgp and whether it can affect the efflux activity of the pump.

Methods

In control rats and in rats treated with the Pgp modulator cyclosporin A (CsA), cerebral accumulation of radiolabeled [¹¹C]celecoxib was investigated by ex vivo biodistribution and micro-positron emission tomography imaging. In addition, the effect of unlabeled celecoxib and CsA (positive control) on the cerebral uptake of the Pgp substrate [¹¹C]verapamil was studied.

Results

[¹¹C]Celecoxib uptake in rat brain was relatively high and homogeneously distributed. Treatment of rats with CsA only marginally increased cerebral tracer uptake, which is most likely due to reduced tracer clearance from plasma. [¹¹C]Verapamil brain uptake was more than 10-fold higher after treatment with CsA. In contrast, a high dose of celecoxib increased cerebral [¹¹C]verapamil uptake only twofold, which was accompanied by a similar increase in tracer concentration in plasma.

Conclusions

This study shows that celecoxib is not a substrate of Pgp and does not substantially affect the Pgp-mediated efflux of [¹¹C]verapamil. Therefore, celecoxib-induced augmentation of the efficacy of chemotherapeutic and neurotropic drugs must be due to another mechanism than modulation of Pgp-mediated drug efflux.

Keywords: Celecoxib, Nonsteroidal anti-inflammatory drug, Positron emission tomography, P-glycoprotein, Blood-brain barrier, [¹¹C]verapamil