1. ¹Department of Pathology, University of Groningen and University Medical Center Groningen, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands
2. ²Department of Medical Oncology, University of Groningen and University Medical Center Groningen, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands
3. ³Department of Radiation and Stress Cell Biology, University of Groningen and University Medical Center Groningen, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands
4. ⁴Department of Nuclear Medicine and Molecular Imaging, University of Groningen and University Medical Center Groningen, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands
5. ⁵Department of Pulmonology, University of Groningen and University Medical Center Groningen, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands

Correspondence: Dr EGE de Vries, E-mail: e.g.e.de.vries@int.umcg.nl

Received 2 March 2007; Revised 30 May 2007; Accepted 1 June 2007; Published online 3 July 2007.

Abstract

The blood–brain barrier (BBB) hampers delivery of several drugs including chemotherapeutics to the brain. The drug efflux pump P-glycoprotein (P-gp), expressed on brain capillary endothelial cells, is part of the BBB. P-gp expression on capillary endothelium decreases 5 days after brain irradiation, which may reduce P-gp function and increase brain levels of P-gp substrates. To elucidate whether radiation therapy reduces P-gp expression and function in the brain, right hemispheres of rats were irradiated with single doses of 2–25 Gy followed by 10 mg kg^-1 of the P-gp substrate cyclosporine A (CsA) intravenously (i.v.), with once 15 Gy followed by CsA (10, 15 or 20 mg kg^-1), or with fractionated irradiation (4 5 Gy) followed by CsA (10 mg kg^-1) 5 days later. Additionally, four groups of three rats received 25 Gy once and were killed 10, 15, 20 or 25 days later. The brains were removed and P-gp detected immunohistochemically. P-gp function was assessed by [¹¹C]carvedilol uptake using quantitative autoradiography. Irradiation increased [¹¹C]carvedilol uptake dose-dependently, to a maximum of 20% above non irradiated hemisphere. CsA increased [¹¹C]carvedilol uptake dose-dependently in both hemispheres, but more (P<0.001) in the irradiated hemisphere. Fractionated irradiation resulted in a lost P-gp expression 10 days after start irradiation, which coincided with increased [¹¹C]carvedilol uptake. P-gp expression decreased between day 15 and 20 after single dose irradiation, and increased again thereafter. Rat brain irradiation results in a temporary decreased P-gp function.