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 x 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 [ C-11] carvedilol uptake using quantitative autoradiography. Irradiation increased [ C-11] carvedilol uptake dose- dependently, to a maximum of 20% above non irradiated hemisphere. CsA increased [ C-11] 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 [ C-11] 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.