Irradiation of rat brain reduces P-glycoprotein expression and function

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 [ 11 C]carvedilol uptake using quantitative autoradiography. Irradiation increased [ 11 C]carvedilol uptake dose-dependently, to a maximum of 20% above non irradiated hemisphere. CsA increased [ 11 C]carvedilol uptake dose-dependently in both hemispheres, but more ( P